Substituted benzaldehyde compounds and methods for their use in increasing tissue oxygenation

ABSTRACT

Provided are substituted benzaldehydes and derivatives thereof that act as allosteric modulators of hemoglobin, methods and intermediates for their preparation, pharmaceutical compositions comprising the modulators, and methods for their use in treating disorders mediate by hemoglobin and disorders that would benefit from increased tissue oxygenation.

REFERENCES TO RELATED APPLICATIONS

The present application claims priority to U.S. Provisional ApplicationNo. 61/581,053, filed Dec. 28, 2011, and U.S. Provisional ApplicationNo. 61/661,320, filed Jun. 18, 2012, the entirety of which areincorporated herein by reference.

FIELD OF THE INVENTION

The present invention generally relates to substituted benzaldehydes andderivatives thereof that act as allosteric modulators of hemoglobin,methods and intermediates for their preparation, pharmaceuticalcompositions comprising the modulators, and methods for their use intreating disorders mediate by hemoglobin and disorders that wouldbenefit from increased tissue oxygenation.

BACKGROUND OF THE INVENTION

Hemoglobin (Hb) is a tetrameric protein in red blood cells thattransports up to four oxygen molecules from the lungs to various tissuesand organs throughout the body. Hemoglobin binds and releases oxygenthrough conformational changes, and is in the tense (T) state when it isunbound to oxygen and in the relaxed (R) state when it is bound tooxygen. The equilibrium between the two conformational states is underallosteric regulation. Natural compounds such as 2,3-bisphosphoglycerate(2,3-BPG), protons, and carbon dioxide stabilize hemoglobin in itsde-oxygenated T state, while oxygen stabilizes hemoglobin in itsoxygenated R state. Other relaxed R states have also been found, howevertheir role in allosteric regulation has not been fully elucidated.

Sickle cell disease is a prevalent disease particularly among those ofAfrican and Mediterranean descent. Sickle hemoglobin (HbS) contains apoint mutation where glutamic acid is replaced with valine, allowing theT state to become susceptible to polymerization to give the HbScontaining red blood cells their characteristic sickle shape. Thesickled cells are also more rigid than normal red blood cells, and theirlack of flexibility can lead to blockage of blood vessels. Certainsynthetic aldehydes have been found to shift the equilibrium from thepolymer forming T state to the non-polymer forming R state (Nnamani etal. Chemistry & Biodiversity Vol. 5, 2008 pp. 1762-1769) by acting asallosteric modulators to stabilize the R state through formation of aSchiff base with an amino group on hemoglobin.

U.S. Pat. No. 7,160,910 discloses 2-furfuraldehydes and relatedcompounds that are also allosteric modulators of hemoglobin. Oneparticular compound 5-hydroxymethyl-2-furfuraldehyde (5HMF) was found tobe a potent hemoglobin modulator both in vitro and in vivo. Transgenicmice producing human HbS that were treated with 5HMF were found to havesignificantly improved survival times when exposed to extreme hypoxia(5% oxygen). Under these hypoxic conditions, the 5HMF treated mice werealso found to have reduced amounts of hypoxia-induced sickled red bloodcells as compared to the non-treated mice.

A need exists for therapeutics that can shift the equilibrium betweenthe deoxygenated and oxygenated states of Hb to treat disorders that aremediated by Hb or by abnormal Hb such as HbS. A need also exists fortherapeutics to treat disorders that would benefit from having Hb in theR state with an increased affinity for oxygen. Such therapeutics wouldhave applications ranging, for example, from sensitizing hypoxic tumorcells that are resistant to standard radiotherapy or chemotherapy due tothe low levels of oxygen in the cell, to treating pulmonary andhypertensive disorders, and to promoting wound healing.

BRIEF SUMMARY OF THE INVENTION

The present invention provides, in one aspect, allosteric modulators ofhemoglobin. In another aspect, provided are pharmaceutical compositionscomprising the allosteric modulators disclosed herein. In other aspects,provided are methods for treating disorders mediated by hemoglobin andmethods for increasing tissue oxygenation for treating disorders thatwould benefit from increased oxygenation, such methods comprisingadministering the allosteric modulators disclosed herein to a subject inneed thereof. In still other aspects, provided are methods for preparingthe allosteric modulators disclosed herein. These and other embodimentsof the invention are more fully described in the description thatfollows.

DETAILED DESCRIPTION OF THE INVENTION I. Definitions

As used herein, the below terms have the following meanings unlessspecified otherwise.

The abbreviations used herein are conventional, unless otherwisedefined: aq=aqueous; Boc=t-butylcarboxy, (Boc)₂O=di-tert-butyldicarbonate, ° C.=degrees celcius, mCPBA=m-chloroperoxybenzoic acid,DCM=dichloromethane (CH2Cl2), DIBAL=diisobutylaluminum hydride,DMF=dimethyl formamide, EtOAc=ethyl acetate, g=gram, H2=hydrogen;H2O=water; HBr=hydrogen bromide; HCl=hydrogen chloride, HPLC=highpressure liquid chromatography, h=hour, LAH=lithium aluminum hydride(LiAlH4); MeCN=acetonitrile; MS=Mass Spectrum, m/z=mass to charge ratio,MHz=Mega Hertz, MeOH=methanol, μM=micromolar, μL=microliter,mg=milligram, mM=millimolar, mmol=millimole, mL=milliliter, mM=minute,M=molar, Na2CO3=sodium carbonate, ng=nanogram, N=Normal, NMR=nuclearmagnetic resonance, Pd/C=palladium on carbon, rp=reverse phase,sat=saturated, rt=room temperature, TEA=triethylamine,THF=tetrahydrofuran, TFA=trifluoroacetic acid, TLC=thin layerchromatography, and TMS=trimethylsilyl.

It is noted here that as used in this specification and the appendedclaims, the singular forms “a,” “an,” and “the” include plural referenceunless the context clearly dictates otherwise.

“Alkoxy” refers to —O(alkyl) where alkyl as defined herein.Representative examples of alkoxy groups include methoxy, ethoxy,t-butoxy, and the like.

“Alkyl,” by itself or as part of another substituent, means, unlessotherwise stated, a straight or branched chain, fully saturatedaliphatic hydrocarbon radical having the number of carbon atomsdesignated. For example, “C₁₋₈alkyl” refers to a hydrocarbon radicalstraight or branched, containing from 1 to 8 carbon atoms that isderived by the removal of one hydrogen atom from a single carbon atom ofa parent alkane. Alkyl includes branched chain isomers of straight chainalkyl groups such as isopropyl, t-butyl, isobutyl, sec-butyl, and thelike. Representative alkyl groups include straight and branched chainalkyl groups having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbonatoms. Further representative alkyl groups include straight and branchedchain alkyl groups having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms.

“Alkenyl” refers to a linear monovalent hydrocarbon radical or abranched monovalent hydrocarbon radical having the number of carbonatoms indicated in the prefix and containing at least one double bond,but no more than three double bonds. For example, C₂₋₈ alkenyl is meantto include, ethenyl, propenyl, 1,3-butadienyl and the like.

“Alkynyl” means a linear monovalent hydrocarbon radical or a branchedmonovalent hydrocarbon radical containing at least one triple bond andhaving the number of carbon atoms indicated in the prefix. The term“alkynyl” is also meant to include those alkyl groups having one triplebond and one double bond. For example, C₂₋₈alkynyl is meant to includeethynyl, propynyl and the like.

The term “allosteric modulators” refers to compounds that bind tohemoglobin to modulate its affinity for oxygen. In one group ofembodiments, the allosteric modulators act to stabilize or destabilize aparticular hemoglobin conformation. In one group of embodiments, themodulators stabilize the relaxed R state. In other embodiments, themodulators destabilize the tense T state. In one group of embodiments,the allosteric modulators can destabilize one conformation whilestabilizing another. In some such embodiments, the modulators stabilizea relaxed R state and destabilize the tense T state. The modulators, inaddition to modulating the affinity of hemoglobin for oxygen, may alsoconfer additional properties to hemoglobin such as increasing itssolubility. The present disclosure is not intended to be limited to themechanism by which the allosteric modulators interact with and regulatehemoglobin. In one group of embodiments, the allosteric modulatorsinhibit the polymerization of HbS and the sickling of red blood cells.In one group of embodiments, the binding of the allosteric modulatorsprovided herein to hemoglobin can occur through covalent or non-covalentinteractions. In one embodiment, the allosteric modulators react throughits aldehyde substituent with an amine group on a hemoglobin amino acidside chain to form a Schiff base.

“Amino” refers to a monovalent radical —NH₂.

“Aryl” by itself or as part of another substituent refers to apolyunsaturated, aromatic, hydrocarbon group containing from 6 to 14carbon atoms, which can be a single ring or multiple rings (up to threerings) which are fused together or linked covalently. Thus the phraseincludes, but is not limited to, groups such as phenyl, biphenyl,anthracenyl, naphthyl by way of example. Non-limiting examples of arylgroups include phenyl, 1-naphthyl, 2-naphthyl and 4-biphenyl.

“Bond” when used as an element in a Markush group means that thecorresponding group does not exist, and the groups of both sides aredirectly linked.

“Cycloalkyl” refers to a saturated or partially saturated cyclic groupof from 3 to 14 carbon atoms and no ring heteroatoms and having a singlering or multiple rings including fused, bridged, and spiro ring systems.The term “cycloalkyl” includes cycloalkenyl groups, a partiallysaturated cycloalkyl ring having at least one site of >C=C<ringunsaturation. Examples of cycloalkyl groups include, for instance,adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, andcyclohexenyl. “C_(u′-v′)cycloalkyl” refers to cycloalkyl groups havingu′ to v′ carbon atoms as ring members. “C_(u′-v′)cycloalkenyl” refers tocycloalkenyl groups having u′ to v′ carbon atoms as ring members.

The term “hemoglobin” as used herein refers to any hemoglobin protein,including normal hemoglobin (Hb) and sickle hemoglobin (HbS).

“Heteroaryl” refers to a cyclic or polycyclic radical having at leastone aromatic ring and from one to five ring heteroatom selected from N,O, and S, and optionally one or more oxo(═O) substituents attached toone or more carbon ring atoms, and wherein the nitrogen and sulfur ringatoms are optionally oxidized. A heteroaryl group can be attached to theremainder of the molecule through a heteroatom or through a carbon atomand can contain 5 to 10 carbon atoms. Heteroaryl groups includepolycyclic aromatic ring(s) fused to non-aromatic cycloalkyl orheterocycloalkyl groups, and where the point of attachment to theremainder of the molecule can be through any suitable ring atom of anyring. In a polycyclic heteroaryl group, the ring heteroatom(s) can be ineither an aromatic or non-aromatic ring or both. The term “aromaticring” include any ring having at least one planar resonance structurewhere 2n+2 pi electrons are delocalized about the ring. Examples ofheteroaryl groups include, but are not limited to, imidazopyridinylgroups, pyrrolopyridinyl groups, pyrazolopyridinyl groups,triazolopyridinyl groups, pyrazolopyrazinyl groups, pyridinyl groups,pyrazinyl groups, oxazolyl groups, imidazolyl groups, triazolyl groups,tetrazolyl groups, pyrazolyl groups, quinolinyl groups, isoquinolinylgroups, indazolyl groups, benzooxazolyl groups, naphthyridinyl groups,and quinoxalinyl groups. Other non-limiting examples of heteroarylgroups include xanthine, hypoxanthine, 5-benzothiazolyl, purinyl,2-benzimidazolyl, benzopyrazolyl, 5-indolyl, azaindole, 1-isoquinolyl,5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, 6-quinolyl1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrazolyl, 3-pyrazolyl,2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl,5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl,4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl,2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl and 4-pyrimidyl. “Bicyclicheteroaryl” refers to a heteroaryl radical that contains two rings.

The term “heterocycloalkyl” refers to a cycloalkyl group containing atleast one ring heteroatom and optionally one or more oxo substituents.As used herein, the term “heteroatom” is meant to include oxygen (O),nitrogen (N), and sulfur (S), wherein the heteroatoms are optionallyoxidized, and the nitrogen atom(s) are optionally quaternized. Eachheterocycle can be attached at any available ring carbon or heteroatom.Each heterocycle may have one or more rings. When multiple rings arepresent, they can be fused together. Each heterocycle typically contains1, 2, 3, 4 or 5, independently selected heteroatoms. Preferably, thesegroups contain 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, 0, 1, 2, 3,4 or 5 nitrogen atoms, 0, 1 or 2 sulfur atoms and 0, 1 or 2 oxygenatoms. More preferably, these groups contain 1, 2 or 3 nitrogen atoms,0-1 sulfur atoms and 0-1 oxygen atoms. Non-limiting examples ofheterocycle groups include morpholin-3-one, piperazine-2-one,piperazin-1-oxide, piperidine, morpholine, piperazine, isoxazoline,pyrazoline, imidazoline, pyrrolidine, and the like.

“Halo” or “halogen” by themselves or as part of another substituent,mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodineatom. Additionally, terms such as “haloalkyl”, are meant to includealkyl in which one or more hydrogen is substituted with halogen atomswhich can be the same or different, in a number ranging from one up tothe maximum number of halogens permitted e.g. for alkyl, (2m′+1), wherem′ is the total number of carbon atoms in the alkyl group. For example,the term “haloC1-8alkyl” is meant to include difluoromethyl,trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, andthe like. The term “haloalkenyl”, and “haloalkynyl” refers to alkenyland alkynyl radicals having one or more halogen atoms. Additionally,term “haloalkoxy” refers to an alkoxy radical substituted with one ormore halogen atoms. In one group of embodiments, the haloakyl,haloalkenyl, haloalkynyl, and haloalkoxy groups have from one to 5 orfrom one to 3 halo atoms. Examples of haloalkoxy groups includedifluoromethoxy and trifluoromethoxy. In one group of embodiments, thehalo atoms of the haloalkenyl and haloalkynyl groups are attached to thealiphatic portions of these groups.

The terms “optional” or “optionally” as used throughout thespecification means that the subsequently described event orcircumstance may but need not occur, and that the description includesinstances where the event or circumstance occurs and instances in whichit does not. For example, “heteroaryl group optionally substituted withan alkyl group means that the alkyl may but need not be present, and thedescription includes situations where the heteroaryl group issubstituted with an alkyl group and situations where the heteroarylgroup is not substituted with the alkyl group.

“Oxo” refers to the divalent atom ═O.

In each of the above embodiments designating a number of atoms e.g.“C₁₋₈” is meant to include all possible embodiments that have one feweratom. Non-limiting examples include C₁₋₄, C₁₋₅, C₁₋₆, C₁₋₇, C₂₋₈, C₂₋₇,C₃₋₈, C₃₋₇ and the like.

The term “pharmaceutically acceptable salts” is meant to include saltsof the active compounds which are prepared with relatively nontoxicacids or bases, depending on the particular substituents found on thecompounds described herein. When compounds of the present inventioncontain relatively acidic functionalities, base addition salts can beobtained by contacting the neutral form of such compounds with asufficient amount of the desired base, either neat or in a suitableinert solvent. Examples of salts derived frompharmaceutically-acceptable inorganic bases include aluminum, ammonium,calcium, copper, ferric, ferrous, lithium, magnesium, manganic,manganous, potassium, sodium, zinc and the like. Salts derived frompharmaceutically-acceptable organic bases include salts of primary,secondary and tertiary amines, including substituted amines, cyclicamines, naturally-occurring amines and the like, such as arginine,betaine, caffeine, choline, N,N′-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine and the like. When compounds of the presentinvention contain relatively basic functionalities, acid addition saltscan be obtained by contacting the neutral form of such compounds with asufficient amount of the desired acid, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable acid additionsalts include those derived from inorganic acids like hydrochloric,hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric,monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,monohydrogensulfuric, hydriodic, or phosphorous acids and the like, aswell as the salts derived from relatively nontoxic organic acids likeacetic, propionic, isobutyric, malonic, benzoic, succinic, suberic,fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric,tartaric, methanesulfonic, and the like. Also included are salts ofamino acids such as arginate and the like, and salts of organic acidslike glucuronic or galactunoric acids and the like (see, e.g., Berge, S.M. et al., “Pharmaceutical Salts,” Journal of Pharmaceutical Science,66:1-19, 1977). Certain specific compounds of the present inventioncontain both basic and acidic functionalities that allow the compoundsto be converted into either base or acid addition salts.

The neutral forms of the compounds may be regenerated by contacting thesalt with a base or acid and isolating the parent compound in theconventional manner. The parent form of the compound differs from thevarious salt forms in certain physical properties, such as solubility inpolar solvents, but otherwise the salts are equivalent to the parentform of the compound for the purposes of the present invention.

The term “pharmaceutically acceptable carrier or excipient” means acarrier or excipient that is useful in preparing a pharmaceuticalcomposition that is generally safe, nontoxic and neither biologicallynor otherwise undesirable, and includes a carrier or excipient that isacceptable for veterinary use as well as human pharmaceutical use. A“pharmaceutically acceptable carrier or excipient” as used in thespecification and claims includes both one and more than one suchcarrier or excipient.

The terms “pharmaceutically effective amount”, “therapeuticallyeffective amount” or “therapeutically effective dose” refers to theamount of the subject compound that will elicit the biological ormedical response of a tissue, system, animal or human that is beingsought by the researcher, veterinarian, medical doctor or otherclinician. The term “therapeutically effective amount” includes thatamount of a compound that, when administered, is sufficient to preventdevelopment of, or alleviate to some extent, one or more of the symptomsof the condition or disorder being treated. The therapeuticallyeffective amount will vary depending on the compound, the disorder orcondition and its severity and the age, weight, etc., of the mammal tobe treated.

“Protecting group” refers to a group of atoms that, when attached to areactive functional group in a molecule, mask, reduce or prevent thereactivity of the functional group. Typically, a protecting group may beselectively removed as desired during the course of a synthesis.Examples of protecting groups can be found in Greene and Wuts,Protective Groups in Organic Chemistry, 3^(rd) Ed., 1999, John Wiley &Sons, NY and Harrison et al., Compendium of Synthetic Organic Methods,Vols. 1-8, 1971-1996, John Wiley & Sons, NY. Representative aminoprotecting groups include, but are not limited to, formyl, acetyl,trifluoroacetyl, benzyl, benzyloxycarbonyl (“CBZ”), tert-butoxycarbonyl(“Boc”), trimethylsilyl (“TMS”), 2-trimethylsilyl-ethanesulfonyl(“TES”), trityl and substituted trityl groups, allyloxycarbonyl,9-fluorenylmethyloxycarbonyl (“FMOC”), nitro-veratryloxycarbonyl(“NVOC”) and the like. Representative hydroxy protecting groups include,but are not limited to, those where the hydroxy group is either acylatedor alkylated such as benzyl and trityl ethers, as well as alkyl ethers,tetrahydropyranyl ethers, trialkylsilyl ethers (e.g., TMS or TIPPSgroups) and allyl ethers.

The term “aldehyde protecting group” refers to any known protectinggroup used to mask the aldehyde functionality. Aldehyde protectinggroups include acetals and hemiacetals. The acetals and hemiacetals canbe prepared from C₁₋₈ alcohols or C₂₋₈ diols. In one group ofembodiments, the aldehyde protecting group is a five or six memberedcyclic acetal formed from condensation of the aldehyde with ethylene orpropylene glycol. In another group of embodiments the aldehydeprotecting group is an imine or hydroxyimine. The aldehyde protectinggroups of the present disclosure also include prodrug groups thatconvert the aldehyde to a prodrug, where the aldehyde is formed in vivoas the active agent under physiological conditions upon administrationof the prodrug. The prodrug group can also serve to increase thebioavailability of the aldehyde. In one group of embodiments, theprodrug group is hydrolyzed in vivo to the aldehyde. In one group ofembodiments, the aldehyde protecting group is a thiazolidine orN-acetylthiazolidine prodrug group. In one group of embodiments, thealdehyde protecting group is a thiazolidine prodrug group disclosed inU.S. Pat. No. 6,355,661. In one group of embodiments the modulatorsprovided herein are condensed with L-cysteine or a L-cysteine derivativeto form the corresponding thiazolidine protected aldehyde prodrug. Inone group of embodiments, the thiazolidine has the formula

wherein R¹¹ is selected from the group consisting of OH, alkoxy,substituted alkoxy, cycloalkoxy, substituted cycloalkoxy, aryloxy,substituted aryloxy, heteroaryloxy, substituted heteroaryloxy, N(R¹³)₂where R¹³ is independently H, alkyl, substituted alkyl, alkenyl,substituted alkenyl, aryl, substituted aryl, heteroaryl, and substitutedheteroaryl; R¹² is H or -L-R¹⁴, where L is carbonyl or sulfonyl; R¹⁴ isselected from the group consisting of alkyl, substituted alkyl, aryl,substituted aryl, heteroaryl, and substituted heteroaryl; the wavy linesignifies the point of attachment to the phenyl ring of the allostericmodulators disclosed herein; and the term “substituted” refers tosubstitution by one or more substituents selected from the groupconsisting of COOH, CHO, oxyacyl, acyloxy, cycloacyloxy, phenol,phenoxy, pyridinyl, pyrrolidinyl, amino, amido, hydroxy, alkoxy,cycloalkoxy, F, Cl, Br, NO₂, cyano, sulfuryl, and the like. In one groupof embodiments, provided are modulators having a thiazolidine protectinggroup where R¹¹ is alkoxy and R¹² is H, or where R¹¹ is OH and R¹² is—C(O)alkyl, or where R¹¹ is NH(heteroaryl) and R¹² is —C(O)alkyl.

The term “sickle cell disease” refers to diseases mediated by sicklehemoglobin (HbS) that results from a single point mutation in thehemoglobin (Hb). Sickle cell diseases includes sickle cell anemia,sickle-hemoglobin C disease (HbSC), sickle beta-plus-thalassaemia(HbS/β⁺) and sickle beta-zero-thalassaemia (HbS/β⁰).

The “subject” is defined herein to include animals such as mammals,including, but not limited to, primates (e.g., humans), cows, sheep,goats, horses, dogs, cats, rabbits, rats, mice and the like. Inpreferred embodiments, the subject is a human.

“Tautomer” refers to alternate forms of a molecule that differ in theposition of a proton, such as enol-keto and imine-enamine tautomers, orthe tautomeric forms of heteroaryl groups containing a —N═C(H)—NH— ringatom arrangement, such as pyrazoles, imidazoles, benzimidazoles,triazoles, and tetrazoles. A person of ordinary skill in the art wouldrecognize that other tautomeric ring atom arrangements are possible.

The terms “treat”, “treating”, “treatment” and grammatical variationsthereof as used herein, includes partially or completely delaying,alleviating, mitigating or reducing the intensity, progression, orworsening of one or more attendant symptoms of a disorder or conditionand/or alleviating, mitigating or impeding one or more causes of adisorder or condition. Treatments according to the invention may beapplied preventively, prophylactically, pallatively or remedially.

The symbol > when used in connection with a substituent signifies thatthe substituent is a divalent substituent attached to two differentatoms through a single atom on the substituent.

The term “wavy line” signifies the point of attachment of thesubstituent to the remainder of the molecule. When the wavy line is notdepicted as being specifically appended to a specific ring atom, thepoint of attachment can be to any suitable atom of the substituent. Forexample, the wavy line in the following structure:

is intended to include, as the point of attachment, any of the sixsubstitutable carbon atoms.

Compounds that have the same molecular formula but differ in the natureor sequence of bonding of their atoms or the arrangement of their atomsin space are termed “isomers”. Isomers that differ in the arrangement oftheir atoms in space are termed “stereoisomers”. “Stereoisomer” and“stereoisomers” refer to compounds that exist in differentstereoisomeric forms if they possess one or more asymmetric centers or adouble bond with asymmetric substitution and, therefore, can be producedas individual stereoisomers or as mixtures. Stereoisomers includeenantiomers and diastereomers. Stereoisomers that are not mirror imagesof one another are termed “diastereomers” and those that arenon-superimposable mirror images of each other are termed “enantiomers”.When a compound has an asymmetric center, for example, it is bonded tofour different groups, a pair of enantiomers is possible. An enantiomercan be characterized by the absolute configuration of its asymmetriccenter and is described by the R- and S-sequencing rules of Cahn andPrelog, or by the manner in which the molecule rotates the plane ofpolarized light and designated as dextrorotatory or levorotatory (i.e.,as (+) or (−)-isomers respectively). A chiral compound can exist aseither individual enantiomer or as a mixture thereof. A mixturecontaining equal proportions of the enantiomers is called a “racemicmixture”. Unless otherwise indicated, the description is intended toinclude individual stereoisomers as well as mixtures. The methods forthe determination of stereochemistry and the separation of stereoisomersare well-known in the art (see discussion in Chapter 4 of ADVANCEDORGANIC CHEMISTRY, 4th edition J. March, John Wiley and Sons, New York,1992) differ in the chirality of one or more stereocenters.

The compounds of the present invention may also contain unnaturalproportions of atomic isotopes at one or more of the atoms thatconstitute such compounds. For example, the compounds may beradiolabeled with isotopes, such as for example deuterium (²H), tritium(³H), iodine-125 (¹²⁵I) or carbon-14 (¹⁴C). All isotopic variations ofthe compounds of the present invention, whether radioactive or not, areintended to be encompassed within the scope of the present invention.

Unless indicated otherwise, the nomenclature of substituents that arenot explicitly defined herein are arrived at by naming the terminalportion of the functionality followed by the adjacent functionalitytoward the point of attachment. For example, the substituent“alkoxyalkyl” refers to an akyl group that is substituted with alkoxyand “hydoxyalkyl” refers to an akyl group that is substituted withhydroxy. For both of these substituents, the point of attachment is atthe alkyl group.

It is understood that the definitions and formulas provided herein arenot intended to include impermissible substitution patterns (e.g.,methyl substituted with 5 fluoro groups). Such impermissiblesubstitution patterns are well known to the skilled artisan.

II. Hemoglobin Modulators

In one group of embodiments, provided is a compound of Formula (I):

or a tautomer or pharmaceutically acceptable salt thereof,

wherein Q is selected from the group consisting of aryl, heteroaryl, andheterocycloalkyl, each optionally substituted with one to three R^(a);

Y is O or CR^(1a)R^(1b), where R^(1a) is H or halo and R^(1b) isselected from the group consisting of H, halo, and OH;

X is selected from the group consisting of O, >CH(CH₂)_(n)R⁸, and C(R⁹)₂where n is 0 or 1, R⁸ is OH, and R⁹ is independently H or halo; or Y—Xtaken together is —NHC(O)— or —C(O)NH—;

R², R³, R⁴, and R⁵ are independently selected from the group consistingof hydrogen, halo, R^(b), OR^(d), O(CH₂)_(z)OR^(d),O(CH₂)_(z)NR^(d)R^(d), OC(O)R^(e), SR^(d), CN, NO₂, CO₂R^(d),CONR^(d)R^(d), C(O)R^(d), OC(O)NR^(d)R^(d), NR^(d)R^(d),NR^(d)C(O)R^(e), NR^(d)C(O)₂R^(e), NR^(d)C(O)NR^(d)R^(d), S(O)R^(e),S(O)₂R^(e), NR^(d)S(O)₂R^(e), S(O)₂NR^(d)R^(d), and N₃, where z is 0, 1,2, 3, 4, 5, or 6; or R⁵ is —(CH₂)_(p)R^(5a) where p is 0 or 1 and R^(5a)is OH;

R⁶ and R⁷ together form oxo or an aldehyde protecting group, or R⁶together with R^(1b), R⁸, or R⁵ forms a cyclic ether where one ofR^(1b), R⁸, or R^(5a) is O, R⁶ is a bond, and R⁷ is selected from thegroup consisting of OH, C₁₋₈alkoxy, and haloC₁₋₈alkoxy;

each R^(a) is independently selected from the group consisting of halo,R^(b), OR^(d), O(CH₂)_(u)OR^(d), O(CH₂)_(u)NR^(d)R^(d),O(CH₂)_(u)NR^(d)C(O)R^(e), O(CH₂)_(u)NR^(d)C(O)₂R^(e),O(CH₂)_(u)NR^(d)S(O)₂R^(e), NH₂, —(CH₂)_(k)OC(O)R^(e), —(CH₂)_(k)SR^(d),CN, NO₂, —(CH₂)_(k)CO₂(C₁₋₈alkyl)OH,—(CH₂)_(k)CO₂(C₁₋₈alkyl)(heteroaryl)C(O)(C₁₋₈alkyl), —(CH₂)_(k)CO₂R^(d),—(CH₂)_(k)CONR^(d)R^(d), —(CH₂)_(k)NR^(d)C(O)R^(e),—(CH₂)_(k)NR^(d)C(O)₂R^(e), —(CH₂)_(k)C(O)R^(d),—(CH₂)_(k)OC(O)NR^(d)R^(d), —NR^(d)(CH₂)_(u)OR^(d),NR^(d)(CH₂)NR^(d)R^(d), —NR^(d)(CH₂)_(u)NR^(d)C(O)R^(e),—NR^(d)(CH₂)_(u)NR^(d)C(O)₂R^(e), —NR^(d)(CH₂)_(u)NR^(d)S(O)₂R^(e),—(CH₂)_(k)NR^(d)C(O)R^(e), —(CH₂)_(k)NR^(d)C(O)₂R^(d),—(CH₂)_(k)NR^(d)C(O)NR^(d)R^(d), —(CH₂)_(k)S(O)R^(e),—(CH₂)_(k)S(O)₂R^(e), —(CH₂)_(k)NR^(d)S(O)₂R^(e),—(CH₂)_(k)S(O)₂NR^(d)R^(d), N₃, —(CH₂)_(k)aryl optionally substitutedwith one to three R^(c), —NR^(d)(CH₂)_(k)aryl optionally substitutedwith one to three R^(c), —(CH₂)_(k)heteroaryl optionally substitutedwith one to three R^(c), —NR^(d)(CH₂)_(k)heteroaryl optionallysubstituted with one to three R^(c), —(CH₂)_(k)heterocycloalkyloptionally substituted with one to three R^(c), and—NR^(d)(CH₂)_(k)heterocycloalkyl optionally substituted with one tothree R^(c) where k is 0, 1, 2, 3, 4, 5, or 6 and u is 1, 2, 3, 4, 5, or6;

each R^(b) is independently selected from the group consisting ofC₁₋₈alkyl, C₂₋₈alkenyl, and C₂₋₈ alkynyl, each optionally independentlysubstituted with one to three halo, OR^(d), or NR^(d)R^(d);

each R^(c) is independently selected from the group consisting of halo,C₁₋₈alkyl, haloC₁₋₈alkyl, C₂₋₈alkenyl, haloC₂₋₈alkenyl, C₂₋₈alkynyl,haloC₂₋₈alkynyl, (CH₂)_(m)OR^(f), OC(O)R^(g), SR^(f), CN, NO₂, CO₂R^(f),CONR^(f)R^(f), C(O)R^(f), OC(O)NR^(f)R^(f), (CH₂)_(m)NR^(f)R^(f),NR^(f)C(O)R^(g), NR^(f)C(O)₂R^(g), NR^(f)C(O)NR^(f)R^(f), S(O)R^(g),S(O)₂R^(g), NR^(f)S(O)₂R^(g), S(O)₂NR^(f)R^(f), N₃, heteroaryloptionally substituted with one to three R^(h), and heterocycloalkyloptionally substituted with one to three R^(h) where m is selected fromthe group consisting of 0, 1, 2, 3, 4, 5, and 6;

each R^(h) is independently selected from the group consisting of halo,C₁₋₈alkyl, haloC₁₋₈alkyl, OR^(j), OC(O)R, SR^(j), NO₂, CO₂R^(j),CONR^(j)R^(j), C(O)R^(j), OC(O)NR^(j)R^(j), NR^(j)R^(j),NR^(j)C(O)R^(t), NR^(j)C(O)₂R^(t), NR^(j)C(O)NR^(j)R^(j), S(O)R^(t),S(O)₂R^(t), NR^(j)S(O)₂R^(t), and S(O)₂NR^(j)R^(j);

R^(d), R^(f), and R^(j) are each is independently selected from thegroup consisting of hydrogen, C₁₋₈ alkyl, haloC₁₋₈alkyl, C₂₋₈ alkenyl,haloC₂₋₈alkenyl, C₂₋₈ alkynyl, and haloC₂₋₈alkynyl; and

R^(e), R^(g), and R^(t) are each is independently selected from thegroup consisting of C₁₋₈alkyl, haloC₁₋₈alkyl, C₂₋₈ alkenyl,haloC₂₋₈alkenyl, C₂₋₈ alkynyl, and haloC₂₋₈alkynyl.

In one group of embodiments, X and Y are not both O.

In one group of embodiments, when X is O, R^(1b) is not OH.

In one group of embodiments, when Y is O, and n is 0, R⁸ is not OH.

In one group of embodiments, when R⁶ and R⁷ together are oxo, Y is CH₂,X is O or CH₂, and R⁵ is H, halo, OH, CHO, or OCH₃, then Q is V or W.

In one group of embodiments, V is selected from the group consisting of

and naphthalene containing three to four ring nitrogen atoms; wherein Vis optionally substituted with one to three R^(a); and

W is selected from the group consisting of pyridin-2-yl, pyridin-3-yl,and pyridine-4-yl,

wherein W is optionally substituted with one to three R^(a) or issubstituted with one to three R^(a) when W is pyridin-2-yl,pyridin-3-yl, or pyridine-4-yl, and wherein the wavy line signifies thepoint of attachment to Y, provided that when V is

optionally substituted with one R^(a), then at least one of R², R³, R⁴,and R⁵ is OR^(d); and provided that when V is

then V is substituted with one to three R^(a).

In one group of embodiments, z is 0. In another group of embodiments, zis 1. In yet another group of embodiments, z is 2. In still anothergroup of embodiments, z is 3. In another group of embodiments, z is 4.In yet another group of embodiments, z is 5. In still another group ofembodiments, z is 6.

In one group of embodiments, provided is a compound of Formula (Ia):

or a tautomer or pharmaceutically acceptable salt thereof,

wherein Q is selected from the group consisting of aryl, heteroaryl, andheterocycloalkyl, each optionally substituted with one to three R^(a);

Y is O or CR^(1a)R^(1b), where R^(1a) is H or halo and R^(1b) isselected from the group consisting of H, halo, and OH;

X is selected from the group consisting of O, >CH(CH₂)_(n)R⁸, and C(R⁹)₂where n is 0 or 1, R⁸ is OH, and R⁹ is independently H or halo;

R², R³, R⁴, and R⁵ are independently selected from the group consistingof hydrogen, halo, R^(b), OR^(d), OC(O)R^(e), SR^(d), CN, NO₂, CO₂R^(d),CONR^(d)R^(d), C(O)R^(d), OC(O)NR^(d)R^(d), NR^(d)R^(d),NR^(d)C(O)R^(e), NR^(d)C(O)₂R^(e), NR^(d)C(O)NR^(d)R^(d), S(O)R^(e),S(O)₂R^(e), NR^(d)S(O)₂R^(e), S(O)₂NR^(d)R^(d), and N₃; or R⁵ is—(CH₂)_(p)R^(5a) where p is 0 or 1 and R^(5a) is OH;

R⁶ and R⁷ together form oxo or an aldehyde protecting group, or R⁶together with R^(1b), R⁸, or R⁵ forms a cyclic ether where one ofR^(1b), R⁸, or R^(5a) is —O—, R⁶ is a bond, and R⁷ is selected from thegroup consisting of OH, C₁₋₈alkoxy, and haloC₁₋₈alkoxy;

each R^(a) is independently selected from the group consisting of halo,R^(b), OR^(d), OC(O)R^(e), SR^(d), CN, NO₂, CO₂R^(d), CONR^(d)R^(d),C(O)R^(d), OC(O)NR^(d)R^(d), NR^(d)C(O)R^(e), NR^(d)C(O)₂R^(d),NR^(d)C(O)NR^(d)R^(d), S(O)R^(e), S(O)₂R^(e), NR^(d)S(O)₂R^(e),S(O)₂NR^(d)R^(d), N₃, aryl optionally substituted with one to threeR^(c), heteroaryl optionally substituted with one to three R^(c), andheterocycloalkyl optionally substituted with one to three R^(c);

each R^(b) is independently selected from the group consisting ofC₁₋₈alkyl, C₂₋₈alkenyl, and C₂₋₈ alkynyl, each optionally independentlysubstituted with one to three halo, OR^(d), or NR^(d)R^(d);

each R^(c) is independently selected from the group consisting of halo,C₁₋₈alkyl, halo C₁₋₈alkyl, C₂₋₈alkenyl, haloC₂₋₈ alkenyl, C₂₋₈alkynyl,haloC₂₋₈alkynyl, (CH₂)_(m)OR^(f), OC(O)R^(g), SR^(f), CN, NO₂, CO₂R^(f),CONR^(f)R^(f), C(O)R^(f), OC(O)NR^(f)R^(f), (CH₂)_(m)NR^(f)R^(f),NR^(f)C(O)R^(g), NR^(f)C(O)₂R^(g), NR^(f)C(O)NR^(f)R^(f), S(O)R^(g),S(O)₂R^(g), NR^(f)S(O)₂R^(g), S(O)₂NR^(f)R^(f), and N₃ where m isselected from the group consisting of 0, 1, 2, 3, 4, 5, and 6;

each R^(d) and R^(f) is independently selected from the group consistingof hydrogen, C₁₋₈ alkyl, haloC₁₋₈alkyl, C₂₋₈ alkenyl, haloC₂₋₈alkenyl,C₂₋₈alkynyl, and haloC₂₋₈alkynyl; and

each R^(e) and R^(g) is independently selected from the group consistingof C₁₋₈alkyl, haloC₁₋₈alkyl, C₂₋₈ alkenyl, haloC₂₋₈alkenyl, C₂₋₈alkynyl, and haloC₂₋₈alkynyl; provided that X and Y are not both O;

provided that when X is O, R^(1b) is not OH;

provided that when Y is O, and n is 0, R⁸ is not OH; and

provided that when R⁶ and R⁷ together are oxo, Y is CH₂, X is O or CH₂,and R⁵ is H, halo, OH, CHO, or OCH₃, then Q is V or W;

V is selected from the group consisting of

and naphthalene containing three to four ring nitrogen atoms; wherein Vis optionally substituted with one to three R^(a); and

W is selected from the group consisting of pyridin-2-yl, pyridin-3-yl,and pyridine-4-yl,

wherein W is optionally substituted with one to three R^(a) or issubstituted with one to three R^(a) when W is pyridin-2-yl,pyridin-3-yl, or pyridine-4-yl, and wherein the wavy line signifies thepoint of attachment to Y, provided that when V is

optionally substituted with one R^(a), then at least one of R², R³, R⁴,and R⁵ is OR^(d).

In one group of embodiments when R⁶ and R⁷ together are oxo, Y is CH₂, Xis O or CH₂, and R⁵ is H, halo, OH, CHO, or OCH₃, Q is not

In one group of embodiments, R⁶ and R⁷ together form oxo.

In one group of embodiments, R⁶ and R⁷ together form a thiazolidine.

In one group of embodiments, z is 0. In another group of embodiments, zis 1. In yet another group of embodiments, z is 2. In still anothergroup of embodiments, z is 3. In another group of embodiments, z is 4.In yet another group of embodiments, z is 5. In still another group ofembodiments, z is 6.

In one group of embodiments, provided is a compound having Formula (Ic),(Id), or (Ie):

or a tautomer or pharmaceutically acceptable salt thereof, wherein R¹⁰is selected from the group consisting of H, C₁₋₈alkyl, andhaloC₁₋₈alkyl.

In one group of embodiments, Q is a heteroaryl or heterocycloalkyl groupoptionally substituted with one to three R^(a).

In one group of embodiments, Q is a bicyclic heteroaryl orheterocycloalkyl group optionally substituted with one to three R^(a).

In one group of embodiments, Q is a bicyclic heteroaryl group optionallysubstituted with one to three R^(a). In one group of embodiments, Q isisoquinolin-4-yl optionally substituted with one to three R^(a) whereinat least one R^(a) is heteroaryl optionally substituted with one tothree R^(c). In one group of embodiments at least one R^(a) isheteroaryl attached to said Q at the ring atom adjacent to ring atombearing Y. In one group of embodiments at least one R^(a) is heteroarylsubstituted with at least one C₁₋₈alkyl. In one group of embodiments atleast one R^(a) heteroaryl is substituted with at least one methyl. Inone group of embodiments at least one R^(a) is pyrazolyl substitutedwith at least one C₁₋₈alkyl. In one group of embodiments at least oneR^(a) is pyrazoyl substituted with at least one methyl. In one group ofembodiments, R^(a) is pyrazol-5-yl. In one group of embodiments, R^(a)is 4-methyl-pyrazol-5-yl.

In one group of embodiments, Q is a bicyclic heteroaryl groupsubstituted with one to three R^(a).

In one group of embodiments, Q is V.

In one group of embodiments, V is selected from the group consisting of

wherein V is optionally substituted with one to three R^(a).

In one group of embodiments, Q is substituted with CONR^(d)R^(d),NR^(d)R^(d), or heteroaryl optionally substituted with one to threeR^(c). In one group of embodiments, Q is substituted with heteroarylhaving one to two nitrogen ring atoms.

In one group of embodiments, Q is W.

In one group of embodiments, Q is selected from the group consisting of

In one group embodiments, at least one R^(a) is heteroaryl optionallysubstituted with one to three R^(c).

In one group of embodiments at least one R^(a) is heteroaryl attached toQ at the ring atom adjacent to ring atom bearing Y.

In one group of embodiments at least one R^(a) is heteroaryl substitutedwith at least one C₁₋₈alkyl. In one group of embodiments at least oneR^(a) heteroaryl is substituted with at least one methyl.

In one group of embodiments at least one R^(a) is pyrazolyl substitutedwith at least one C₁₋₈alkyl. In one group of embodiments at least oneR^(a) is pyrazoyl substituted with at least one C₁₋₈alkyl. In one groupof embodiments, at least one R^(a) is pyrazol-5-yl. In one group ofembodiments, at least one R^(a) is 4-methyl-pyrazol-5-yl.

In one group of embodiments, Q is pyridin-2-yl, pyridin-3-yl, orpyridine-4-yl, said Q is optionally substituted with one to three R^(a)wherein at least one R^(a) is heteroaryl optionally substituted with oneto three R^(c). In one group of embodiments at least one R^(a) isheteroaryl attached to said Q at the ring atom adjacent to ring atombearing Y. In one group of embodiments at least one R^(a) is heteroarylsubstituted with at least one C₁₋₈alkyl. In one group of embodiments atleast one R^(a) heteroaryl is substituted with at least one methyl. Inone group of embodiments at least one R^(a) is pyrazolyl substitutedwith at least one C₁₋₈alkyl. In one group of embodiments at least oneR^(a) is pyrazoyl substituted with at least one methyl. In one group ofembodiments, R^(a) is pyrazol-5-yl. In one group of embodiments, R^(a)is 4-methyl-pyrazol-5-yl.

In one group of embodiments, Q is substituted with at least one R^(a)selected from the group consisting of —(CH₂)_(k)OH, —(CH₂)_(k)NH₂,—(CH₂)_(k)NH(C₁₋₈alkyl), —(CH₂)_(k)N(C₁₋₈alkyl)(C₁₋₈alkyl),—(CH₂)_(k)NHC(O)(C₁₋₈alkyl), —(CH₂)_(k)N(C₁₋₈alkyl)C(O)(C₁₋₈alkyl),—(CH₂)_(k)NHC(O)₂(C₁₋₈alkyl), —(CH₂)_(k)N(C₁₋₈alkyl)C(O)₂(C₁₋₈alkyl),—(CH₂)_(k)NHS(O)₂(C₁₋₈alkyl), —(CH₂)_(k)N(C₁₋₈alkyl)S(O)₂(C₁₋₈alkyl),and —(CH₂)_(k)heterocycloalkyl optionally substituted with one to threeR^(c). In some embodiments the heterocycloalkyl group is morpholino orpiperazinyl optionally substituted with alkyl, —C(O)C₁₋₈alkyl,—C(O)₂C₁₋₈alkyl, or —S(O)₂C₁₋₈alkyl.

In one group of embodiments, Q is substituted with at least one R^(a)selected from the group consisting of —NR^(d)(CH₂)_(u)OH,—NR^(d)(CH₂)_(u)NH₂, —NR^(d)(CH₂)_(u)NH(C₁₋₈alkyl),—NR^(d)(CH₂)_(u)N(C₁₋₈alkyl)(C₁₋₈alkyl),—NR^(d)(CH₂)_(u)NHC(O)(C₁₋₈alkyl),—NR^(d)(CH₂)_(u)N(C₁₋₈alkyl)C(O)(C₁₋₈alkyl),—NR^(d)(CH₂)_(u)NHC(O)₂(C₁₋₈alkyl),—NR^(d)(CH₂)_(u)N(C₁₋₈alkyl)C(O)₂(C₁₋₈alkyl),—NR^(d)(CH₂)_(u)NHS(O)₂(C₁₋₈alkyl),—NR^(d)(CH₂)_(u)N(C₁₋₈alkyl)S(O)₂(C₁₋₈alkyl), and—NR^(d)(CH₂)_(k)heterocycloalkyl optionally substituted with one tothree R^(c) where u is 1, 2, 3, 4, 5, or 6 and k is 0, 1, 2, 3, 4, 5, or6. In some embodiments, R^(d) is H or C₁₋₈alkyl. In some embodiments theheterocycloalkyl group is morpholino or piperazinyl optionallysubstituted with alkyl, —C(O)C₁₋₈alkyl, —C(O)₂C₁₋₈alkyl, or—S(O)₂C₁₋₈alkyl.

In one group of embodiments, Q is substituted with at least one R^(a)selected from the group consisting of O(CH₂)_(u)OH, O(CH₂)_(u)NH₂,O(CH₂)_(u)NH(C₁₋₈alkyl), O(CH₂)_(u)N(C₁₋₈alkyl)(C₁₋₈alkyl),O(CH₂)_(u)NHC(O)(C₁₋₈alkyl), O(CH₂)_(u)N(C₁₋₈alkyl)C(O)(C₁₋₈alkyl),O(CH₂)_(u)NHC(O)₂(C₁₋₈alkyl), O(CH₂)_(u)N(C₁₋₈alkyl)C(O)₂(C₁₋₈alkyl),O(CH₂)_(u)NHS(O)₂(C₁₋₈alkyl), O(CH₂)_(u)N(C₁₋₈alkyl)S(O)₂(C₁₋₈alkyl),and O(CH₂)_(u)heterocycloalkyl optionally substituted with one to threeR^(c) where u is 1, 2, 3, 4, 5, or 6. In some embodiments theheterocycloalkyl group is morpholino or piperazinyl optionallysubstituted with alkyl, —C(O)C₁₋₈alkyl, —C(O)₂C₁₋₈alkyl, or—S(O)₂C₁₋₈alkyl.

In one group of embodiments, W is pyridin-2-yl, pyridin-3-yl, orpyridine-4-yl, said W substituted with CN or CONR^(d)R^(d).

In one group of embodiments, R² is H.

In one group of embodiments, R³ is H.

In one group of embodiments, R⁵ is H.

In one group of embodiments, R⁴ is C₁₋₈alkoxy.

In one group of embodiments, R², R³, R⁵ are H and R⁴ is C₁₋₈alkoxy.

In one group of embodiments, R⁴ is methoxy.

In one group of embodiments, R⁴ is haloalkoxy. In one group ofembodiments, R⁴ is OCHF₂. In one group of embodiments, R⁴ is OCF₃.

In one group of embodiments, R², R³, R⁴, and R⁵ are H.

In one group of embodiments, one of R², R³, R⁴, and R⁵ is selected fromthe group consisting of —O(CH₂)_(z)OH, —O(CH₂)_(z)O(C₁₋₈alkyl),—O(CH₂)_(z)NH₂, —O(CH₂)_(z)NH(C₁₋₈alkyl), and—O(CH₂)N(C₁₋₈alkyl)(C₁₋₈alkyl) where z is 0, 1, 2, 3, 4, 5, or 6.

In one group of embodiments, X is O.

In one group of embodiments, X is CH₂.

In one group of embodiments, X is C(R⁹)₂ and at least one of R⁹ is F.

In one group of embodiments, Y is CH₂.

In one group of embodiments, Y is CR^(1a)R^(1b) and at least one ofR^(1a) or R^(1b) is F.

In one group of embodiments, z is 0. In another group of embodiments, zis 1. In yet another group of embodiments, z is 2. In still anothergroup of embodiments, z is 3. In another group of embodiments, z is 4.In yet another group of embodiments, z is 5. In still another group ofembodiments, z is 6.

In other embodiments, the invention provide a compound according toFormula (Ib):

or a tautomer or pharmaceutically acceptable salt thereof,

wherein Q is selected from the group consisting of aryl, heteroaryl, andheterocycloalkyl, each optionally substituted with one to three R^(a);

Y is O or CH₂;

X is O or CH₂;

R² and R³ are independently selected from the group consisting ofhydrogen, halo, R^(b), OR^(d), —O(CH₂)_(z)OR^(d),—O(CH₂)_(z)NR^(d)R^(d), OC(O)R^(e), SR^(d), CN, NO₂, CO₂R^(d),CONR^(d)R^(d), C(O)R^(d), OC(O)NR^(d)R^(d), NR^(d)R^(d),NR^(d)C(O)R^(e), NR^(d)C(O)₂R^(e), NR^(d)C(O)NR^(d)R^(d), S(O)R^(e),S(O)₂R^(e), NR^(d)S(O)₂R^(e), S(O)₂NR^(d)R^(d), and N₃, where z is 0, 1,2, 3, 4, 5, or 6; or R⁵ is —(CH₂)_(p)R^(5a) where p is 0 or 1 and R^(5a)is OH;

R⁴ is selected from the group consisting of hydrogen and OR^(d);

R⁵ is selected from the group consisting of hydrogen, halo, and OR^(d);

R⁶ and R⁷ together form oxo or an aldehyde protecting group;

each R^(a) is independently selected from the group consisting of halo,R^(b), OR^(d), O(CH₂)_(u)OR^(d), O(CH₂)_(u)NR^(d)R^(d),O(CH₂)_(u)NR^(d)C(O)R^(e), O(CH₂)_(u)NR^(d)C(O)₂R^(e),O(CH₂)_(u)NR^(d)S(O)₂R^(e), NH₂, —(CH₂)_(k)OC(O)R^(e), —(CH₂)_(k)SR^(d),CN, NO₂, —(CH₂)_(k)CO₂(C₁₋₈alkyl)OH,—(CH₂)_(k)CO₂(C₁₋₈alkyl)(heteroaryl)C(O)(C₁₋₈alkyl), —(CH₂)_(k)CO₂R^(d),—(CH₂)_(k)CONR^(d)R^(d), —(CH₂)_(k)NR^(d)C(O)R^(e),—(CH₂)_(k)NR^(d)C(O)₂R^(e), —(CH₂)_(k)C(O)R^(d),—(CH₂)_(k)OC(O)NR^(d)R^(d), —NR^(d)(CH₂)_(u)OR^(d),—NR^(d)(CH₂)_(u)NR^(d)R^(d), —NR^(d)(CH₂)_(u)NR^(d)C(O)R^(e),—NR^(d)(CH₂)_(u)NR^(d)C(O)₂R^(e), —NR^(d)(CH₂)_(u)NR^(d)S(O)₂R^(e),—(CH₂)_(k)NR^(d)C(O)R^(e), —(CH₂)_(k)NR^(d)C(O)₂R^(d),—(CH₂)_(k)NR^(d)C(O)NR^(d)R^(d), —(CH₂)_(k)S(O)R^(e),—(CH₂)_(k)S(O)₂R^(e), —(CH₂)_(k)NR^(d)S(O)₂R^(e),—C(O)(CH₂)_(k)NR^(d)S(O)₂R^(e), —(CH₂)_(k)C(O)NR^(d)S(O)₂R^(e),—(CH₂)_(k)S(O)₂NR^(d)R^(d), N₃, —(CH₂)_(k)aryl optionally substitutedwith one to three R^(c), —NR^(d)(CH₂)_(k)aryl optionally substitutedwith one to three R^(c), —(CH₂)_(k)heteroaryl optionally substitutedwith one to three R^(c), —NR^(d)(CH₂)_(k)heteroaryl optionallysubstituted with one to three R^(c), —(CH₂)_(k)heterocycloalkyloptionally substituted with one to three R^(c), and—NR^(d)(CH₂)_(k)heterocycloalkyl optionally substituted with one tothree R^(c) where k is 0, 1, 2, 3, 4, 5, or 6 and u is 1, 2, 3, 4, 5, or6;

each R^(b) is independently selected from the group consisting ofC₁₋₈alkyl, C₂₋₈alkenyl, and C₂₋₈ alkynyl, each optionally independentlysubstituted with one to three halo, OR^(d), or NR^(d)R^(d);

each R^(c) is independently selected from the group consisting of halo,C₁₋₈alkyl, haloC₁₋₈ alkyl, C₂₋₈alkenyl, haloC₂₋₈alkenyl, C₂₋₈alkynyl,haloC₂₋₈alkynyl, (CH₂)_(m)OR^(f), OC(O)R⁵, SR^(f), CN, NO₂,(CH₂)_(m)CO₂R^(f), CONR^(f)R^(f), C(O)R^(f), OC(O)NR^(f)R^(f),(CH₂)_(m)NR^(f)R^(f), NR^(f)C(O)R^(g), NR^(f)C(O)₂R^(g),NR^(f)C(O)NR^(f)R^(f), S(O)R^(g), S(O)₂R^(g), NR^(f)S(O)₂R^(g),S(O)₂NR^(f)R^(f), N₃, (R^(f))_(m)SiC₁₋₈alkyl, heteroaryl optionallysubstituted with one to three R^(h), cycloalkyl optionally substitutedwith one to three R^(h), and heterocycloalkyl optionally substitutedwith one to three R^(h) where m is selected from the group consisting of0, 1, 2, 3, 4, 5, and 6;

each R^(h) is independently selected from the group consisting of halo,C₁₋₈alkyl, haloC₁₋₈alkyl, OR^(j), OC(O)R, SR^(j), NO₂, CO₂R^(j),CONR^(j)R^(j), C(O)R^(j), OC(O)NR^(j)R^(j), NR^(j)R^(j),NR^(j)C(O)R^(t), NR^(j)C(O)₂R^(t), NR^(j)C(O)NR^(j)R^(j), S(O)R^(t),S(O)₂R^(t), NR^(j)S(O)₂R^(t), and S(O)₂NR^(j)R^(j);

R^(d), R^(f), and R^(f) are each independently selected from the groupconsisting of hydrogen, C₁₋₈alkyl, haloC₁₋₈alkyl, C₂₋₈ alkenyl,haloC₂₋₈alkenyl, C₂₋₈ alkynyl, and haloC₂₋₈alkynyl; and

R^(e), R^(g), and R^(t) are each independently selected from the groupconsisting of C₁₋₈alkyl, haloC₁₋₈alkyl, C₂₋₈ alkenyl, haloC₂₋₈alkenyl,C₂₋₈ alkynyl, and haloC₂₋₈alkynyl;

provided that X and Y are not both O;

provided that at least one of R⁴ and R⁵ is H;

provided that if R⁴ is OR^(d), then Q is not phenyl, pyridinyl, orimidazo[1,2-a]pyridin-2-yl, R^(a) is not oxo, oxido, or halo, and X isO,

provided that if R⁵ is OR^(d), then R^(a) is not oxo, oxido, or halo;and

provided that if R²-R⁵ are H, then Q is not phenyl.

In one group of embodiments, the invention provides a compound offormula Ib, or a tautomer or pharmaceutically acceptable salt thereof,wherein R⁶ and R⁷ together form oxo.

In one group of embodiments, the invention provides a compound offormula Ib, or a tautomer or pharmaceutically acceptable salt thereof,wherein R⁵ is selected from the group consisting of hydrogen and OR^(d).

In one group of embodiments, the invention provides a compound offormula Ib, or a tautomer or pharmaceutically acceptable salt thereof,wherein R⁵ is selected from the group consisting of hydroxy and fluoro.

In one group of embodiments, the invention provides a compound offormula Ib, wherein R² and R³ are independently selected from the groupconsisting of hydrogen, R^(b), OR^(d), O(CH₂)_(z)OR^(d),O(CH₂)_(z)NR^(d)R^(d), OC(O)R^(e), CO₂R^(d), CONR^(d)R^(d), andC(O)R^(d), where z is 1, 2, or 3.

In one group of embodiments, the invention provides a compound offormula Ib, wherein R² and R³ are H.

In one group of embodiments, the invention provides a compound offormula Ib, wherein Q is selected from the group consisting of:

and wherein Q is optionally substituted with one to three R^(a).

In one group of embodiments, the invention provides a compound offormula Ib, wherein Q is selected from the group consisting of animidazopyridinyl group, a pyrrolopyridinyl group, a pyrazolopyridinylgroup, a triazolopyridinyl group, a pyrazolopyrazinyl group, a pyridinylgroup, a pyrazinyl group, an oxazolyl group, an imidazolyl group, atriazolyl group, a tetrazolyl group, a pyrazolyl group, a quinolinylgroup, an isoquinolinyl group, and indazolyl group, a benzooxazolylgroup, a naphthyridinyl group, a quinoxalinyl group; and wherein Q isoptionally substituted with one to three R^(a).

In one group of embodiments, the invention provides a compound offormula Ib, wherein z is 0. In another group of embodiments, z is 1. Inyet another group of embodiments, z is 2. In still another group ofembodiments, z is 3. In another group of embodiments, z is 4. In yetanother group of embodiments, z is 5. In still another group ofembodiments, z is 6.

In other embodiments, the invention provide a compound according toFormula Ic:

or a tautomer or pharmaceutically acceptable salt thereof, wherein:

-   -   Y is O or CH₂;    -   X is O or CH₂;    -   Q is selected from the group consisting of:    -   i) imidazopyridinyl, methylimidazopyridinyl, indazolyl,        pyrrolopyridinyl, pyrrolopyrazinyl, pyrazolopyridinyl,        pyrazolopyrazinyl, and quinolinyl, each of which is optionally        substituted with one to three R^(a); wherein        -   R², R³, R⁴, and R⁵, are independently selected from the            group consisting of hydrogen, halo, R^(b), OR^(d),            O(CH₂)_(z)OR^(d), O(CH₂)_(z)NR^(d)R^(d), OC(O)R^(e), SR^(d),            CN, NO₂, CO₂R^(d), CONR^(d)R^(d), C(O)R^(d),            OC(O)NR^(d)R^(d), NR^(d)R^(d), NR^(d)C(O)R^(e),            NR^(d)C(O)₂R^(e), NR^(d)C(O)NR^(d)R^(d), S(O)R^(e),            S(O)₂R^(e), NR^(d)S(O)₂R^(e), S(O)₂NR^(d)R^(d), and N₃ where            z is 1, 2, or 3; and    -   ii) pyridinyl and piperidinyl, each of which is optionally        substituted with one to three R^(a); wherein        -   R², R³, and R⁴ are independently selected from the group            consisting of hydrogen, halo, R^(b), OR^(d),            O(CH₂)_(z)OR^(d), O(CH₂)_(z)NR^(d)R^(d), OC(O)R^(e), SR^(d),            CN, NO₂, CO₂R^(d), CONR^(d)R^(d), C(O)R^(d),            OC(O)NR^(d)R^(d), NR^(d)R^(d), NR^(d)C(O)R^(e),            NR^(d)C(O)₂R^(e), NR^(d)C(O)NR^(d)R^(d), S(O)R^(e),            S(O)₂R^(e), NR^(d)S(O)₂R^(e), S(O)₂NR^(d)R^(d), and N₃ where            z is 1, 2, or 3; and        -   R⁵ is selected from the group consisting of halo and OR^(d);    -   R⁶ and R⁷ together form oxo or an aldehyde protecting group;    -   each R^(a) is independently selected from the group consisting        of halo, oxo, R^(b), OR^(d), O(CH₂)_(u)OR^(d),        O(CH₂)_(u)NR^(d)R^(d), O(CH₂)_(u)NR^(d)C(O)R^(e),        O(CH₂)_(u)NR^(d)C(O)₂R^(e), O(CH₂)_(u)NR^(d)S(O)₂R^(e), NH₂,        —(CH₂)_(k)OC(O)R^(e), —(CH₂)_(k)SR^(d), CN, NO₂,        —(CH₂)_(k)CO₂(C₁₋₈alkyl)OH,        —(CH₂)_(k)CO₂(C₁₋₈alkyl)(heteroaryl)C(O)(C₁₋₈alkyl),        —(CH₂)_(k)CO₂R^(d), —(CH₂)_(k)CONR^(d)R^(d),        —(CH₂)_(k)NR^(d)C(O)R^(e), —(CH₂)_(k)R^(d)C(O)₂R^(e),        —(CH₂)_(k)C(O)R^(d), —(CH₂)_(k)OC(O)NR^(d)R^(d),        —NR^(d)(CH₂)_(u)OR^(d), —NR^(d)(CH₂)_(u)NR^(d)R^(d),        —NR^(d)(CH₂)_(u)NR^(d)C(O)R^(e),        —NR^(d)(CH₂)_(u)NR^(d)C(O)₂R^(e),        —NR^(d)(CH₂)_(u)NR^(d)S(O)₂R^(e), —(CH₂)_(k)NR^(d)C(O)R^(e),        —(CH₂)_(k)NR^(d)C(O)₂R^(d), —(CH₂)_(k)NR^(d)C(O)NR^(d)R^(d),        —(CH₂)_(k)S(O)R^(e), —(CH₂)_(k)S(O)₂R^(e),        —(CH₂)_(k)NR^(d)S(O)₂R^(e), —C(O)(CH₂)_(k)NR^(d)S(O)₂R^(e),        —(CH₂)_(k)C(O)NR^(d)S(O)₂R^(e), —(CH₂)_(k)S(O)₂NR^(d)R^(d), N₃,        —(CH₂)_(k)aryl optionally substituted with one to three R^(c),        —NR^(d)(CH₂)_(k)aryl optionally substituted with one to three        R^(c), —(CH₂)_(k)heteroaryl optionally substituted with one to        three R^(c), —NR^(d)(CH₂)_(k)heteroaryl optionally substituted        with one to three R^(c), —(CH₂)_(k)heterocycloalkyl optionally        substituted with one to three R^(c), and        —NR^(d)(CH₂)_(k)heterocycloalkyl optionally substituted with one        to three R^(c) where k is 0, 1, 2, 3, 4, 5, or 6 and u is 1, 2,        3, 4, 5, or 6;    -   each R^(b) is independently selected from the group consisting        of C₁₋₈alkyl, C₂₋₈ alkenyl, and C₂₋₈alkynyl, each optionally        independently substituted with one to three halo, OR^(d), or        NR^(d)R^(d);    -   each R^(c) is independently selected from the group consisting        of halo, C₁₋₈alkyl, haloC₁₋₈alkyl, C₂₋₈alkenyl, haloC₂₋₈alkenyl,        C₂₋₈alkynyl, haloC₂₋₈alkynyl, (CH₂)_(m)OR^(f), OC(O)R^(g),        SR^(f), CN, NO₂, (CH₂)_(m)CO₂R^(f), CONR^(f)R^(f), C(O)R^(f),        OC(O)NR^(f)R^(f), (CH₂)_(m)NR^(f)R^(f), NR^(f)C(O)R^(g),        NR^(f)C(O)₂R^(g), NR^(f)C(O)NR^(f)R^(f), S(O)R^(g), S(O)₂R^(g),        NR^(f)S(O)₂R^(g), S(O)₂NR^(f)R^(f), N₃, (R^(f))_(m)SiC₁₋₈alkyl,        heteroaryl optionally substituted with one to three R^(h),        cycloalkyl optionally substituted with one to three R^(h), and        heterocycloalkyl optionally substituted with one to three R^(h)        where m is selected from the group consisting of 0, 1, 2, 3, 4,        5, and 6;    -   each R^(h) is independently selected from the group consisting        of halo, C₁₋₈alkyl, haloC₁₋₈alkyl, OR^(j), OC(O)R, SR^(j), NO₂,        CO₂R^(j), CONR^(j)R^(j), C(O)R^(j), OC(O)NR^(j)R^(j),        NR^(j)R^(j), NR^(j)C(O)R^(t), NR^(j)C(O)₂R^(t),        NR^(j)C(O)NR^(j)R^(j), S(O)R^(t), S(O)₂R^(t), NR^(j)S(O)₂R^(t),        and S(O)₂NR^(j)R^(j);    -   R^(d), R^(f), and R^(j) are each independently selected from the        group consisting of hydrogen, C₁₋₈ alkyl, haloC₁₋₈alkyl, C₂₋₈        alkenyl, haloC₂₋₈alkenyl, C₂₋₈ alkynyl, and haloC₂₋₈alkynyl; and    -   R^(e), R^(g), and R^(t) are each independently selected from the        group consisting of C₁₋₈alkyl, haloC₁₋₈alkyl, C₂₋₈alkenyl,        haloC₂₋₈alkenyl, C₂₋₈ alkynyl, and haloC₂₋₈ alkynyl.

In one group of embodiments, the invention provides a compound offormula Ic, wherein Q is selected from the group consisting ofimidazo[1,5-a]pyridin-8-yl, imidazo[1,5-a]pyridin-6-yl,imidazo[1,5-a]pyridin-5-yl, imidazo[1,2-a]pyridin-8-yl,imidazo[1,2-a]pyridin-7-yl, imidazo[1,2-a]pyridin-6-yl,imidazo[1,2-a]pyridin-5-yl, imidazo[1,2-a]pyridin-3-yl,8-methylimidazo[1,2-a]pyridin-2-yl, indazol-4-yl,pyrrolo[2,3-b]pyridin-4-yl, pyrrolo[1,2-a]pyrazin-6-yl,pyrrolo[1,2-a]pyrazin-4-yl, pyrazolo[3,4-b]pyridin-4-yl,pyrazolo[1,5-a]pyrazin-3-yl, and quinolin-5-yl, each of which isoptionally substituted with one to three R^(a).

In one group of embodiments, the invention provides a compound offormula Ic, wherein z is 1. In another group of embodiments, z is 2. Instill another group of embodiments, z is 3.

In one group of embodiments, the invention provides a compound wherein:Y is CH₂, and X is CH₂.

In one group of embodiments, the invention provides a compound offormula Ic, wherein R² is selected from the group consisting of H andOR^(d);

-   -   R³ is selected from the group consisting of H, CN, halo, and        OR^(d);    -   R⁴ is selected from the group consisting of H, CN, and OR^(d):        and    -   R⁵ is H.

In one group of embodiments, the invention provides a compound offormula Ic, wherein R⁴ is methoxy.

In one group of embodiments, the invention provides a compound offormula Ic, wherein Q is selected from the group consisting ofpyridine-3-yl and piperidin-1-yl.

In one group of embodiments, the invention provides a compound offormula Ic, wherein R⁵ is selected from the group consisting of hydroxyand fluoro.

In one group of embodiments, the invention provides a compound offormula Ic, wherein R⁶ and R⁷ together form oxo.

In one group of embodiments, a compound is selected from Table 1 belowor a tautomer or pharmaceutically acceptable salt thereof.

TABLE 1 Compound Structure Name 1

2-(imidazo[1,2-a]pyridin-8- ylmethoxy)-5-methoxybenzaldehyde 2

4-formyl-3-(imidazo[1,2-a]pyridin-8- ylmethoxy)benzonitrile 3

2-(imidazo[1,2-a]pyridin-8- ylmethoxy)-4-methoxybenzaldehyde 4

2-(imidazo[1,2-a]pyridin-6- ylmethoxy)-5-methoxybenzaldehyde 5

2-(imidazo[1,2-a]pyridin-2- ylmethoxy)-5-methoxybenzaldehyde 6

2-(imidazo[1,5-a]pyridin-8- ylmethoxy)-4-methoxybenzaldehyde 7

2-(imidazo[1,5-a]pyridin-8- ylmethoxy)-5-methoxybenzaldehyde 8

2-(imidazo[1,2-a]pyridin-7- ylmethoxy)-5-methoxybenzaldehyde 9

2-(imidazo[1,2-a]pyridin-3- ylmethoxy)-5-methoxybenzaidehyde 10

5-methoxy-2-(quinolin-5- ylmethoxy)benzaldehyde 11

5-bromo-2-(imidazo[1,2-a]pyridin-8- ylmethoxy)benzaldehyde 12

4-chloro-2-(imidazo[1,2-a]pyridin-8- ylmethoxy)benzaldehyde 13

2-(imidazo[1,2-a]pyridin-8- ylmethoxy)benzaldehyde 14

4-fluoro-2-(imidazo[1,2-a]pyridin-8- ylmethoxy)benzaldehyde 15

2-(imidazo[1,2-a]pyridin-8- ylmethoxy)-3-methoxybenzaldehyde 16

2-(imidazo[1,2-a]pyridin-8- ylmethoxy)-5-methylbenzaldehyde 17

5-methoxy-2-(pyrrolo[1,2-a]pyrazin-4- ylmethoxy)benzaldehyde 18

2-(imidazo[1,5-a]pyridin-6- ylmethoxy)-4-methoxybenzaldehyde 19

2-(imidazo[1,5-a]pyridin-5- ylmethoxy)-5-methoxybenzaldehyde 20

3-formyl-4-(imidazo[1,5-a]pyridin-5- ylmethoxy)benzonitrile 21

2-((1H-pyrrolo[2,3-b]pyridin-4- yl)methoxy)-5-methoxybenzaldehyde 22

5-ethyl-2-(imidazo[1,2-a]pyridin-8- ylmethoxy)benzaldehyde 23

5-methoxy-2-((1-methyl-1H-indazol-4- yl)methoxy)benzaldehyde 24

5-methoxy-2-((8-methylimidazo[1,2- a]pyridin-2-yl)methoxy)benzaldehyde25

2-((1H-indazol-4-yl)methoxy)-5- methoxybenzaldehyde 26

2-((1H-pyrrolo[2,3-b]pyridin-4- yl)methoxy)-5-methoxybenzaldehyde 27

3-formyl-4-(imidazo[1,2-a]pyridin-8- ylmethoxy)benzonitrile 28

5-methoxy-2-(pyrrolo[1,2-a]pyrazin-6- ylmethoxy)benzaldehyde 29

6-((2-formyl-4- methoxyphenoxy)methyl)pyrrolo[1,2-a]pyrazine-7-carbonitrile 30

6-((2-formyl-4- methoxyphenoxy)methyl)pyrrolo[1,2-a]pyrazine-7-carboxamide 31

2-((1H-pyrazolo[3,4-b]pyridin-4- yl)methoxy)-5-methoxybenzaldehyde 32

5-methoxy-2-(pyrazolo[1,5-a]pyrazin- 3-ylmethoxy)benzaldehyde 33

5-methoxy-2-(pyrrolo[1,2-a]pyrazin-6- ylmethoxy)benzaldehyde 34

2-(imidazo[1,5-a]pyridin-6- ylmethoxy)-5-methoxybenzaldehyde 35

3-formyl-4-(imidazo[1,2-a]pyridin-8- ylmethoxy)benzonitrile 36

3-(imidazo[1,2-a]pyridin-8-ylmethyl)- 1,3-dihydroisobenzofuran-1-ol 37

2-(imidazo[1,2-a]pyridin-5- ylmethoxy)-5-methoxybenzaldehyde 38

N-(2-formyl-4- methoxyphenyl)imidazo[1,2- a]pyridine-8-carboxamide 39

N-(2-formylphenyl)imidazo[1,2- a]pyridine-8-carboxamide 40

2-formyl-N-(imidazo[1,2-a]pyridin-8- yl)benzamide 41

5-methoxy-2-(pyridin-3- ylmethoxy)benzaldehyde 42

4-((2-formyl-3- hydroxyphenoxy)methyl)benzoic acid 43

2-hydroxy-6-((2-(1-isopropyl-1H- pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde 44

2-((3-(2H-tetrazol-5-yl)benzyl)oxy)-6- hydroxybenzaldehyde 45

2-((4-(2H-tetrazol-5-yl)benzyl)oxy)-6- hydroxybenzaldehyde 46

methyl 4-((2- formylphenoxy)methyl)benzoate 47

4-((2-formylphenoxy)methyl)benzoic acid 48

methyl 3-((2- formylphenoxy)methyl)benzoate 49

2-bromo-3-((2-(1-isopropyl-1H- pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde 50

2-hydroxy-6-((2-(1-(2,2,2- trifluoroethyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde 51

2-hydroxy-6-((2-(1-(3,3,3- trifluoropropyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde 52

2-fluoro-6-((2-(1-(2,2,2-trifluoroethyl)- 1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde 53

2-fluoro-6-((2-(1-(3,3,3- trifluoropropyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde 54

2-fluoro-6-((2-(1-isopropyl-1H- pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde 55

1-(2-formyl-3- hydroxyphenethyl)piperidine-4- carboxylic acid

In one group of embodiments, the compound is selected from:

-   2-(imidazo[1,2-a]pyridin-8-ylmethoxy)-5-methoxybenzaldehyde,-   2-(imidazo[1,2-a]pyridin-2-ylmethoxy)-5-methoxybenzaldehyde,-   2-(imidazo[1,5-a]pyridin-8-ylmethoxy)-5-methoxybenzaldehyde,-   5-methoxy-2-(quinolin-5-ylmethoxy)benzaldehyde,-   5-methoxy-2-((1-methyl-1H-indazol-4-yl)methoxy)benzaldehyde,-   5-methoxy-2-((8-methylimidazo[1,2-a]pyridin-2-yl)methoxy)benzaldehyde,-   2-((1H-indazol-4-yl)methoxy)-5-methoxybenzaldehyde,-   5-methoxy-2-(pyridin-3-ylmethoxy)benzaldehyde,-   2-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-5-methoxybenzaldehyde,-   2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde,-   2-((3-(2H-tetrazol-5-yl)benzyl)oxy)-6-hydroxybenzaldehyde,-   2-((4-(2H-tetrazol-5-yl)benzyl)oxy)-6-hydroxybenzaldehyde,-   methyl 4-((2-formylphenoxy)methyl)benzoate,-   4-((2-formylphenoxy)methyl)benzoic acid,-   methyl 3-((2-formylphenoxy)methyl)benzoate,-   2-bromo-3-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde,-   2-hydroxy-6-((2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde,-   2-hydroxy-6-((2-(1-(3,3,3-trifluoropropyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde,-   2-fluoro-6-((2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde,-   2-fluoro-6-((2-(1-(3,3,3-trifluoropropyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde,-   2-fluoro-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde,    and-   1-(2-formyl-3-hydroxyphenethyl)piperidine-4-carboxylic acid, or a    tautomer or pharmaceutically acceptable salt thereof.

In one group of embodiments, provided is a compound in any of theExamples or Tables. In another group of embodiments, provided are anycombinations of subembodiments as disclosed herein including anycombination of elements disclosed herein including the a selection ofany single elements.

In one group of embodiments, provided is a pharmaceutical compositioncomprising a compound of any of the above embodiments or a tautomer orpharmaceutically acceptable salt thereof.

In one group of embodiments, provided is a pharmaceutical compositioncomprising a compound that is

or a pharmaceutically acceptable salt thereof.

The compounds of the present invention may be prepared by known organicsynthesis techniques, including the methods described in more detail inthe Examples.

In one group of embodiments, provided is an intermediate compound usedin the preparation of the compounds disclosed herein.

In one group of embodiments, provided are methods for preparing thecompounds disclosed herein.

For example, Scheme I shows a synthetic route for the synthesis of thecompounds of Formula (I) where X is O and Y is CH₂. Phenol 1.1 iscontacted with intermediate 1.2 in the presence of base under etherforming conditions to give ether 1.3, where Lg represents a leavinggroup such as a halogen leaving group. Conversely, when X is O and Y isCH₂, the compounds of Formula (I) can be prepared using the appropriatestarting materials where the OH moiety of intermediate 1.1 is replacedwith a leaving group and the Lg group of intermediate 1.2 is replacedwith an OH group.

Scheme II shows an example of a synthetic route for the synthesis of thecompounds of Formula (I) where X and Y are CH₂. Alkene 2.1 is contactedwith alkene 2.2 under metathesis forming conditions in the presence ofan appropriate transition metal catalyst. Suitable catalysts includeruthenium catalysts such as Grubbs' catalyst. Product 2.3 is thenhydrogenated to give compound 2.4.

Scheme III shows an example of a synthetic route for the synthesis ofthe compounds of Formula (I) where R⁶ together with R^(1b) form a cyclicether. Compound 3.1, is reacted with diethylphosphite and a base such assodium methoxide to give intermediate 3.2, that is then condensed withaldehyde 3.3 to give alkene 3.4. Treatment of the alkene with H₂ underhydrogenation conditions gives lactone 3.4, which is then reduced with asuitable reducing agent such as LiBHEt₃ to give cyclic hemiacetal 3.5.

Scheme IV shows an example of synthesis of the compounds of Formula (I)where Q is pyridine-3-yl and R^(a) heteroaryl. Acid 4.1 is reduced toalcohol 4.2 using known methods such as by forming the anhydride (e.g.treatment with triethylamine and i-butyl chloroformate) followed byreduction with NaBH₄. Alcohol 4.2 is converted to chloride 4.3 such asby treatment with thionyl chloride. Coupling of the halide with alcohol4.4 under ether forming conditions gives the precursor 4.5 that can befunctionalized with a variety to heteroaryl R^(a) groups. For example,4.5 can be coupled with pyrazole 4.6 under known organometallic couplingconditions (e.g. Pd(PPh₃)₄) to give 4.7, where PG is a nitrogenprotecting group such as a silyl protecting group that can be removed togive the product 4.8.

One skilled in the art will recognize that in certain embodiments it maybe advantageous to use a protecting group strategy. The protecting groupcan be removed using methods known to those skilled in the art.

In one group of embodiments, certain of the compounds disclosed hereinmay generally be utilized as the free base. Alternatively, certain ofthe compounds may be used in the form of acid addition salts.

It is understood that in another group of embodiments, any of the aboveembodiments may also be combined with other embodiments listed herein,to form other embodiments of the invention. Similarly, it is understoodthat in other embodiments, listing of groups includes embodimentswherein one or more of the elements of those groups is not included.

III. Compositions and Methods of Administration

Depending on the intended mode of administration, the pharmaceuticalcompositions may be in the form of solid, semi-solid or liquid dosageforms, preferably in unit dosage form suitable for single administrationof a precise dosage. In addition to an effective amount of the activecompound(s), the compositions may contain suitablepharmaceutically-acceptable excipients, including adjuvants whichfacilitate processing of the active compounds into preparations whichcan be used pharmaceutically. “Pharmaceutically acceptable excipient”refers to an excipient or mixture of excipients which does not interferewith the effectiveness of the biological activity of the activecompound(s) and which is not toxic or otherwise undesirable to thesubject to which it is administered.

For solid compositions, conventional excipients include, for example,pharmaceutical grades of mannitol, lactose, starch, magnesium stearate,sodium saccharin, talc, cellulose, glucose, sucrose, magnesiumcarbonate, and the like. Liquid pharmacologically administrablecompositions can, for example, be prepared by dissolving, dispersing,etc., an active compound as described herein and optional pharmaceuticaladjuvants in water or an aqueous excipient, such as, for example, water,saline, aqueous dextrose, and the like, to form a solution orsuspension. If desired, the pharmaceutical composition to beadministered may also contain minor amounts of nontoxic auxiliaryexcipients such as wetting or emulsifying agents, pH buffering agentsand the like, for example, sodium acetate, sorbitan monolaurate,triethanolamine sodium acetate, triethanolamine oleate, etc.

For oral administration, the composition will generally take the form ofa tablet or capsule, or it may be an aqueous or nonaqueous solution,suspension or syrup. Tablets and capsules are preferred oraladministration forms. Tablets and capsules for oral use will generallyinclude one or more commonly used excipients such as lactose and cornstarch. Lubricating agents, such as magnesium stearate, are alsotypically added. When liquid suspensions are used, the active agent maybe combined with emulsifying and suspending excipients. If desired,flavoring, coloring and/or sweetening agents may be added as well. Otheroptional excipients for incorporation into an oral formulation includepreservatives, suspending agents, thickening agents, and the like.

Injectable formulations can be prepared in conventional forms, either asliquid solutions or suspensions, solid forms suitable for solubilizationor suspension in liquid prior to injection, or as emulsions or liposomalformulations. The sterile injectable formulation may also be a sterileinjectable solution or a suspension in a nontoxic parenterallyacceptable diluent or solvent. Among the acceptable vehicles andsolvents that may be employed are water, Ringer's solution and isotonicsodium chloride solution. In addition, sterile, fixed oils, fatty estersor polyols are conventionally employed as solvents or suspending media.

The pharmaceutical compositions of this invention may also be formulatedin lyophilized form for parenteral administration. Lyophilizedformulations may be reconstituted by addition of water or other aqueousmedium and then further diluted with a suitable diluent prior to use.The liquid formulation is generally a buffered, isotonic, aqueoussolution. Examples of suitable diluents are isotonic saline solution, 5%dextrose in water, and buffered sodium or ammonium acetate solution.Pharmaceutically acceptable solid or liquid excipients may be added toenhance or stabilize the composition, or to facilitate preparation ofthe composition.

Typically, a pharmaceutical composition of the present invention ispackaged in a container with a label, or instructions, or both,indicating use of the pharmaceutical composition in the treatment of theindicated disease.

The pharmaceutical composition may additionally contain one or moreother pharmacologically active agents in addition to a compound of thisinvention.

Dosage forms containing effective amounts of the modulators are withinthe bounds of routine experimentation and within the scope of theinvention. A therapeutically effective dose may vary depending upon theroute of administration and dosage form. The representative compound orcompounds of the invention is a formulation that exhibits a hightherapeutic index. The therapeutic index is the dose ratio between toxicand therapeutic effects which can be expressed as the ratio between LD₅₀and ED₅₀. The LD₅₀ is the dose lethal to 50% of the population and theED₅₀ is the dose therapeutically effective in 50% of the population. TheLD₅₀ and ED₅₀ are determined by standard pharmaceutical procedures inanimal cell cultures or experimental animals. It should be understoodthat a specific dosage and treatment regimen for any particular patientwill depend upon a variety of factors, including the activity of thespecific compound employed, the age, body weight, general health, sexand diet of the patient, and the time of administration, rate ofexcretion, drug combination, judgment of the treating physician andseverity of the particular disease being treated. The amount of activeingredient(s) will also depend upon the particular compound and othertherapeutic agent, if present, in the composition.

IV. Methods

In one group of embodiments, provided is a method for increasing tissueoxygenation, the method comprising administering to a subject in needthereof a therapeutically effective amount of a compound of any of theabove embodiments or a tautomer or pharmaceutically acceptable saltthereof.

In one group of embodiments, provided is a method for treating acondition associated with oxygen deficiency, the method comprisingadministering to a subject in need thereof a therapeutically effectiveamount of a compound of any of the above embodiments or a tautomer orpharmaceutically acceptable salt thereof.

In one group of embodiments, provided is a method for treating sicklecell disease, cancer, a pulmonary disorder, stroke, high altitudesickness, an ulcer, a pressure sore, Alzheimer's disease, acuterespiratory disease syndrome, and a wound, the method comprisingadministering to a subject in need thereof a therapeutically effectiveamount of a compound of any of the above embodiments or a tautomer orpharmaceutically acceptable salt thereof.

In one group of embodiments, provided is a method for increasing tissueoxygenation or for treating a condition associated with oxygendeficiency, said method comprising administering to a subject in needthereof a therapeutically effective amount of a compound Formula (II):

or a tautomer or pharmaceutically acceptable salt thereof,

wherein Q is selected from the group consisting of aryl, heteroaryl, andheterocycloalkyl, each optionally substituted with one to three R^(a);

Y is O or CR^(1a)R^(1b), where R^(1a) is H or halo and R^(1b) isselected from the group consisting of H, halo, and OH;

X is selected from the group consisting of O, >CH(CH₂)_(n)R⁸, and C(R⁹)₂where n is 0 or 1, R⁸ is OH, and R⁹ is independently H or halo; or Y—Xtaken together is —NHC(O)— or —C(O)NH—;

R², R³, R⁴, and R⁵ are independently selected from the group consistingof hydrogen, halo, R^(b), OR^(d), —O(CH₂)_(z)OR^(d),—O(CH₂)_(z)NR^(d)R^(d), OC(O)R^(e), SR^(d), CN, NO₂, CO₂R^(d),CONR^(d)R^(d), C(O)R^(d), OC(O)NR^(d)R^(d), NR^(d)R^(d),NR^(d)C(O)R^(e), NR^(d)C(O)₂R^(e), NR^(d)C(O)NR^(d)R^(d), S(O)R^(e),S(O)₂R^(e), NR^(d)S(O)₂R^(e), S(O)₂NR^(d)R^(d), and N₃, where z is 0, 1,2, 3, 4, 5, or 6; or R⁵ is —(CH₂)_(p)R^(5a) where p is 0 or 1 and R^(5a)is OH;

R⁶ and R⁷ together form oxo or an aldehyde protecting group, or R⁶together with R^(1b), R⁸, or R⁵ forms a cyclic ether where one ofR^(1b), R⁸, or R^(5a) is O, R⁶ is a bond, and R⁷ is selected from thegroup consisting of OH, C₁₋₈alkoxy, and haloC₁₋₈alkoxy;

each R^(a) is independently selected from the group consisting of halo,R^(b), OR^(d), O(CH₂)_(u)OR^(d), O(CH₂)_(u)NR^(d)R^(d),O(CH₂)_(u)NR^(d)C(O)R^(c), O(CH₂)_(u)NR^(d)C(O)₂R^(e),O(CH₂)_(u)NR^(d)S(O)₂R^(e), NH₂, —(CH₂)_(k)OC(O)R^(e), —(CH₂)_(k)SR^(d),CN, NO₂, —(CH₂)_(k)CO₂(C₁₋₈alkyl)OH,—(CH₂)_(k)CO₂(C₁₋₈alkyl)(heteroaryl)C(O)(C₁₋₈alkyl), —(CH₂)_(k)CO₂R^(d),—(CH₂)_(k)CONR^(d)R^(d), —(CH₂)_(k)NR^(d)C(O)R^(e),—(CH₂)_(k)NR^(d)C(O)₂R^(e), —(CH₂)_(k)C(O)R^(d),—(CH₂)_(k)OC(O)NR^(d)R^(d), —NR^(d)(CH₂)_(u)OR^(d),—NR^(d)(CH₂)_(u)NR^(d)R^(d), —NR^(d)(CH₂)_(u)NR^(d)C(O)R^(e),—NR^(d)(CH₂)NR^(d)C(O)₂R^(e), —NR^(d)(CH₂)_(u)NR^(d)S(O)₂R^(e),—(CH₂)_(k)NR^(d)C(O)R^(e), —(CH₂)_(k)NR^(d)C(O)₂R^(d),—(CH₂)_(k)NR^(d)C(O)NR^(d)R^(d), —(CH₂)_(k)S(O)R^(e),—(CH₂)_(k)S(O)₂R^(e), —(CH₂)_(k)NR^(d)S(O)₂R^(e),—(CH₂)_(k)S(O)₂NR^(d)R^(d), N₃, —(CH₂)_(k)aryl optionally substitutedwith one to three R^(c), —NR^(d)(CH₂)_(k)aryl optionally substitutedwith one to three R^(c), —(CH₂)_(k)heteroaryl optionally substitutedwith one to three R^(c), —NR^(d)(CH₂)_(k)heteroaryl optionallysubstituted with one to three R^(c), —(CH₂)_(k)heterocycloalkyloptionally substituted with one to three R^(c), and—NR^(d)(CH₂)_(k)heterocycloalkyl optionally substituted with one tothree R^(c) where k is 0, 1, 2, 3, 4, 5, or 6 and u is 1, 2, 3, 4, 5, or6;

each R^(b) is independently selected from the group consisting ofC₁₋₈alkyl, C₂₋₈alkenyl, and C₂₋₈ alkynyl, each optionally independentlysubstituted with one to three halo, OR^(d), or NR^(d)R^(d);

each R^(c) is independently selected from the group consisting of halo,C₁₋₈alkyl, haloC₁₋₈alkyl, C₂₋₈alkenyl, haloC₂₋₈ alkenyl, C₂₋₈alkynyl,haloC₂₋₈alkynyl, (CH₂)_(m)OR^(f), OC(O)R^(g), SR^(f), CN, NO₂, CO₂R^(f),CONR^(f)R^(f), C(O)R^(f), OC(O)NR^(f)R^(f), (CH₂)_(m)NR^(f)R^(f),NR^(f)C(O)R^(g), NR^(f)C(O)₂R^(g), NR^(f)C(O)NR^(f)R^(f), S(O)R^(g),S(O)₂R^(g), NR^(f)S(O)₂R^(g), S(O)₂NR^(f)R^(f), N₃, heteroaryloptionally substituted with one to three R^(h), and heterocycloalkyloptionally substituted with one to three R^(h) where m is selected fromthe group consisting of 0, 1, 2, 3, 4, 5, and 6;

R^(d), R^(f), and R^(j) are each independently selected from the groupconsisting of hydrogen, C₁₋₈ alkyl, haloC₁₋₈alkyl, C₂₋₈ alkenyl,haloC₂₋₈alkenyl, C₂₋₈ alkynyl, and haloC₂₋₈alkynyl; and

R^(e), R^(g), and R^(t) are each independently selected from the groupconsisting of C₁₋₈alkyl, haloC₁₋₈alkyl, C₂₋₈ alkenyl, haloC₂₋₈alkenyl,C₂₋₈ alkynyl, and haloC₂₋₈alkynyl;

provided that X and Y are not both O;

provided that when X is O, R^(b) is not OH;

provided that when Y is O, and n is 0, R⁸ is not OH; and

provided that when R⁶ and R⁷ together are oxo, one R², R³, R⁴, and R⁵ ismethoxy or ethoxy, and the other of R², R³, R⁴, and R⁵ is H, then Q isnot unsubstituted pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl.

In one group of embodiments, provided is a method wherein z is 0. Inanother group of embodiments, z is 1. In yet another group ofembodiments, z is 2. In still another group of embodiments, z is 3. Inanother group of embodiments, z is 4. In yet another group ofembodiments, z is 5. In still another group of embodiments, z is 6.

V. Examples

The following examples are offered to illustrate, but not to limit, theclaimed invention.

Preparative Examples

The starting materials and reagents used in preparing these compoundsgenerally are either available from commercial suppliers, such asAldrich Chemical Co., or are prepared by methods known to those skilledin the art following procedures set forth in references such as Fieserand Fieser's Reagents for Organic Synthesis, Wiley & Sons: New York,1967-2004, Volumes 1-22; Rodd's Chemistry of Carbon Compounds, ElsevierScience Publishers, 1989, Volumes 1-5 and Supplementals; and OrganicReactions, Wiley & Sons: New York, 2005, Volumes 1-65.

The starting materials and the intermediates of the synthetic reactionschemes can be isolated and purified if desired using conventionaltechniques, including but not limited to, filtration, distillation,crystallization, chromatography, and the like. Such materials can becharacterized using conventional means, including physical constants andspectral data.

Unless specified to the contrary, the reactions described hereinpreferably are conducted under an inert atmosphere at atmosphericpressure at a reaction temperature range of from about −78° C. to about150° C., more preferably from about 0° C. to about 125° C., and mostpreferably and conveniently at about room (or ambient) temperature,e.g., about 20° C. to about 75° C.

Referring to the examples that follow, compounds of the presentinvention were synthesized using the methods described herein, or othermethods known in the art.

Example 1 Preparation of2-(imidazo[1,5-a]pyridin-8-ylmethoxy)-5-methoxybenzaldehyde

Step 1

To a cold solution of 3-ethoxycarbonylpyridine (25 g, 165.4 mmol, I eq)in DCM was slowly added mCPBA (70% wt, 198.5 mmol) and the reactionmixture was stirred at rt overnight. Reaction was cooled and dilutedwith DCM and then neutralized with slow addition of sat. NaHCO₃. Aqueouslayer was washed with DCM (3×) and the combined organic layer was driedand evaporated to give a residue, which was purified by columnchromatography (EtOAc/MeOH) to give 3-ethoxycarbonylpyridine N-oxide(13.6 g). MS: exact mass calculated for C₈H₉NO₃, 167.06; m/z found, 168[M+H]⁺.

Step 2

To a solution of 3-ethoxycarbonylpyridine N-oxide in 330 mL of DCM wereadded trimethylsilyl cyanide (TMSCN) (11.0 g, 65.9 mmol, 1.0 eq) anddimethylcarbamoyl chloride (7.1 g, 65.9 mmol, 1.0 eq) and the reactionmixture was stirred at rt for 2 days. Then 10% K₂CO₃ was slowly added tomake the reaction mixture basic. Organic layer was separated, dried andevaporated to provide the crude, which was purified by columnchromatography to provide compounds A (5.7 g) and B (3.5 g).

Steps 3 and 4

To a solution of ethyl 2-cyano-3-pyridinecarboxylate (2.5 g) and conc.HCl (5 mL) in 150 mL ethanol was added 10% Pd/C (wet, 250 mg) and thereaction mixture was hydrogenated using a hydrogen balloon and stirredfor 12 h. The reaction was filtered through celite and ethanol wasevaporated to give ethyl 2-(aminomethyl)-3-pyridinecarboxylate HCl as awhite solid which was used in the next step without furtherpurification.

A mixture of 44.8 mL of acetic anhydride and 19.2 mL of formic acid washeated in a 50-60 OC oil bath temperature for 3 h and then cooled to rtto give formic-acetic anhydride, which was then slowly added to thesolid ethyl 2-(aminomethyl)-3-pyridinecarboxylate HCl and then stirredat rt for 8 h. Excess reagent was evaporated to give a residue, whichwas neutralized by very slow addition of sat. NaHCO₃ solution. Solutionwas extracted with DCM, dried and evaporated to provide ethylimidazo[1,5-a]pyridine-8-carboxylate as a yellow solid (crude weight 2.7g). MS: exact mass calculated for C₁₀H₁₀N₂O₂, 190.07; m/z found, 191[M+H]⁺.

Steps 5 and 6

To a cold solution of lithium aluminum hydride (1.62 g, 42.4 mmol, 4.0eq) in THF (50 mL) was added the crude ethylimidazo[1,5-a]pyridine-8-carboxylate (2.7 g, 14.2 mmol, 1.0 eq) and thereaction mixture was heated at reflux for 2 h. The reaction was cooledand water (1.7 mL), 15% NaOH (1.7 mL) and water (5.1 mL) were slowlyadded. Solution was diluted with excess EtOAc and stirred at rt for 30min. The solution was filtered and the solid was washed with ethylacetate. Organic layers were combined, dried and solvent was removed togive crude imidazo[1,5-a]pyridine-8-methanol, which was purified bycolumn chromatography (EtOAc/Hexane). MS: exact mass calculated forC₈H₈N₂O, 148.06; m/z found, 149 [M+H]⁺.

To a solution of imidazo[1,5-a]pyridine-8-methanol (800 mg) inchloroform (50 mL) was slowly added thionyl chloride (10 mL) and thereaction mixture was stirred at rt for 8 h. Chloroform was removed andthe residue was then taken in toluene and toluene was evaporated (3×) togive a solid, which was used in the next step without furtherpurification. MS: exact mass calculated for C₈H₇ClN₂, 166.03; m/z found,167 [M+H]⁺.

Step 7

To a solution of chloride (1.25 mmol, 1.0 eq), and phenol (1.25 mmol,1.0 eq) in DMF (10 mL) was added K₂CO₃ (3.0 eq) and the reaction mixturewas heated at 80-90° C. for 5 h. Solvent was removed and the residue waspurified by column chromatography (EtOAc/MeOH). NMR (400 MHz, CDCl₃): δ3.82 (s, 3H), 5.45 (s, 2H), 6.58 (m, 1H), 6.81 (m, 1H), 7.03 (s, 1H),7.12 (m, 1H), 7.35 (m, 1H), 7.50 (s, 1H), 7.95 (m, 1H), 8.18 (s, 1H),10.58 (s, 1H); MS: exact mass calculated for C₁₆H₁₄N₂O₃, 282.10; m/zfound, 283 [M+H]⁺.

Example 2 Preparation of 2-(imidazo[1,5-a]pyridin-8-ylmethoxy)-4-methoxybenzaldehyde

The title compound was prepared using 2-hydroxy-4-methoxybenzaldehyde ina similar manner as in Example 1. NMR (400 MHz, CDCl₃): δ 3.85 (s, 3H),5.50 (s, 2H), 6.50-6.60 (m, 3H), 6.88 (s, 1H), 7.48 (s, 1H), 7.88 (m,2H), 8.18 (s, 1H), 10.58 (s, 1H); MS: exact mass calculated forC₁₆H₁₄N₂O₃, 282.10; m/z found, 283 [M+H]⁺.

Example 3 Preparation of2-(imidazo[1,5-a]pyridin-6-ylmethoxy)-5-methoxybenzaldehyde

Steps 1 and 2

To a solution of ethyl 6-cyano-3-pyridinecarboxylate (3.75 g) and conc.HCl (7.5 mL) in 225 mL ethanol was added 10% Pd/C (wet, 375 mg) and thereaction mixture was hydrogenated using hydrogen balloon and stirred for12 h. Solution was filtered through celite and ethanol was evaporated togive ethyl 6-(aminomethyl)-3-pyridinecarboxylate HCl as a white solid,which was used in the next step without further purification.

A mixture of 67.2 mL of acetic anhydride and 28.8 mL of formic acid washeated at 50-60° C. oil bath temperature for 3 h and then cooled to rtto give formic-acetic anhydride, which was then slowly added into thesolid ethyl 2-(aminomethyl)-3-pyridinecarboxylate HCl and then stirredat rt for 8 h. Excess reagent was evaporated to give a residue, whichwas neutralized by very slow addition of sat NaHCO₃ solution. Solutionwas extracted with DCM, dried and evaporated to provideimidazo[1,5-a]pyridine as a yellow solid. MS: exact mass calculated forC₁₀H₁₀N₂O₂, 190.07; m/z found, 191 [M+H]⁺.

Steps 3 and 4

To a cold solution of lithium aluminum hydride (1.0 g, 26.3 mmol, 2.0eq) in THF (40 mL) was added the crude ethyl imidazopyridine carboxylate(2.5 g, 13.2 mmol, 1.0 eq) and the reaction mixture was stirred at rtfor 2 h. Reaction was cooled and water (1.7 mL), 15% NaOH (1.7 mL) andwater (5.1 mL) were slowly added. Solution was next diluted with excessEtOAc and stirred at rt for 30 min. The solution was filtered and thesolid was washed with ethyl acetate. Organic layers were combined, driedand solvent was removed to give crude imidazo[1,5-a]pyridine-8-methanol,which was purified by column chromatography (EtOAc/Hexane). MS: exactmass calculated for C₈H₈N₂O, 148.06; m/z found, 149 [M+H]⁺.

To a solution of imidazopyridine methanol (700 mg, 4.7 mmol, 1.0 eq) inchloroform (20 mL) was slowly added thionyl chloride (1.7 mL) and thereaction mixture was stirred at rt for 8 h. Chloroform was removed andthe residue was then taken up in toluene. Toluene was evaporated (3×) togive a solid (550 mg), which was used in the next step without furtherpurification.

Step 5

To a solution of chloride (1.25 mmol, 1.0 eq), and phenol (1.25 mmol,1.0 eq) in DMF (10 mL) was added K₂CO₃ (3.0 eq) and the reaction mixturewas heated at 80-90° C. for 5 h. Solvent was removed and the residue waspurified by column chromatography (EtOAc/MeOH).MS: exact mass calculatedfor C₁₆H₁₄N₂O₃, 282.10; m/z found, 283 [M+H]⁺.

Example 4 Preparation of 2-(imidazo[1,5-a]pyridin-6-ylmethoxy)-4-methoxybenzaldehyde

The title compound was prepared using 2-hydroxy-4-methoxybenzaldehyde ina similar manner as in Example 3.

Example 5 Preparation of methyl imidazo[1,2-a]pyridine-8-carboxylate

To a solution of methyl 2-amino-pyridine-3-carboxylate (5 g, 35 mmol,1.0 eq) in ethanol (250 mL) was added NaHCO₃ (5.08 g) andchloroacetaldehyde in water (35 mL of 45% in water, 148 mmol, 4.5 eq).The reaction mixture was heated at reflux for 18 h. Solvent was removedand the residue was basified with Na₂CO₃ and then extracted with DCM.Organic layers were combined and evaporated to give a residue, which waspurified by column to give the titled compound.

Example 6 Preparation of imidazo[1,2-a]pyridin-8-ylmethanol

To a cold solution of methyl imidazo[1,2-a]pyridine-8-carboxylate e(5.55 g, 31.53 mmol, 1 eq) in THF (100 mL) was added LAH in ether (1 Msolution in ether, 4 equiv.) and then stirred at rt for 6 h. Thereaction mixture was cooled to 0° C. and quenched with water/15%NaOH/water. Reaction mixture was diluted with ethyl acetate and stirredat room temperature for 15 min and then filtered. The solid was washedwith ethanol and the organic layers were combined, dried and evaporatedto give the alcohol, which was purified by column chromatography toyield the desired product in 40% yield.

Example 7 Preparation of 8-(chloromethyl)imidazo[1,2-a]pyridine

A mixture of imidazo[1,2-a]pyridin-8-ylmethanol (800 mg) and excessthionyl chloride was stirred at 70-80° C. for 8 h. Excess thionylchloride was removed under vacuum. The residue was then diluted withtoluene and evaporated. This procedure was repeated 3 times.

Example 8 Preparation of2-(imidazo[1,2-a]pyridin-8-ylmethoxy)-5-methoxybenzaldehyde

To a solution of the crude 8-(chloromethyl)imidazo[1,2-a]pyridine (6.8mmol, 1 eq) and 2-hydroxy-5-methoxybenzaldehyde (1.3 g, 8.1 mmol, 1.2eq) in DMF (20 mL) was added potassium carbonate (2.8 g, 20.4 mmol, 3eq) and the reaction mixture was heated at 85-90° C. for 5 h. DMF wasremoved under vacuum and the residue was taken in ethyl acetate andfiltered. The solid was washed with additional ethyl acetate, and thendried and evaporated to give the crude, which was purified by columnchromatography (EtOAc/Hexane) to yield the desired compound in 45%yield. NMR (400 MHz, CDCl₃): δ 3.80 (s, 3H), 5.60 (s, 2H), 6.85 (d, 1H),7.12 (d, 2H), 7.36 (m, 2H), 7.66 (m, 2H), 8.14 (m, 1H), 10.58 (s, 1H);MS: exact mass calculated for C₁₆H₁₄N₂O₃, 282.10; m/z found, 283 [M+H]⁺.

Example 9 Preparation of 2-(imidazo[1,2-a]pyridin-8-ylmethoxy)-4-methoxybenzaldehyde

The title compound was prepared using 2-hydroxy-4-methoxybenzaldehyde ina similar manner as in Example 3. NMR (400 MHz, CDCl₃): δ 3.88 (s, 3H),5.65 (s, 2H), 6.58 (m, 1H), 6.68 (s, 1H), 6.88 (m, 1H), 7.42 (m, 1H),7.66 (m, 2H), 7.83 (m, 1H), 8.14 (m, 1H), 10.45 (s, 1H); MS: exact masscalculated for C₁₆H₁₄N₂O₃, 282.10; m/z found, 283 [M+H]⁺.

Example 10 Preparation of5-methoxy-2-((1-methyl-1H-indazol-4-yl)methoxy)benzaldehyde (Compound115)

Step 1

To a mixture of 1-methyl-1H-indazole-4-carbaldehyde (180 mg, 1.12 mol)in THF (10 mL) was added NaBH₄ (85 mg, 2.24 mmol) at rt. The reactionmixture was stirred at rt for 1 h, acidified to pH 3, and extracted withEtOAc. The combined organic layer was washed with saturated sodiumbicarbonate solution and brine, dried over Na₂SO₄, filtered, andconcentrated to give a crude solid (191 mg), which was used for nextstep without further purification.

Step 2

To (1-methyl-1H-indazol-4-yl)methanol (191 mg) in DCM (5 mL) was addedSOCl₂ (2 mL) at rt. The reaction mixture was stirred at rt for 4 h andconcentrated to dryness. The crude solid was suspended in toluene andconcentrated to dryness. The process was repeated three times and driedunder vacuum to give an off-white solid (210 mg), which was used fornext step without further purification.

Step 3

A mixture of 2-hydroxy-5-methoxybenzaldehyde (170 mg, 1.12 mmol),4-(chloromethyl)-1-methyl-1H-indazole (1.12 mmol), and K₂CO₃ (618 mg,4.48 mmol) was reflux in CH₃CN (20 mL) for 2 h. The mixture was filteredand the solid was washed with DCM. The filtrate was concentrated andpurified on silica gel using a mixture of EtOAc and MeOH as eluent togive 5-methoxy-2-((1-methyl-1H-indazol-4-yl)methoxy)benzaldehyde (215mg, 81% for three steps) as a white solid. ¹H NMR (400 MHz; DMSO)δ=10.39 (s, 1H), 8.20 (d, 1H), 7.63 (d, 1H) 7.36-7.64 (m, 2H), 7.23-7.29(m, 2H), 7.18 (d, 1H), 5.58 (s, 2H), 4.06 (s, 3H), 3.34 (s, 3H). LRMS(M+H⁺) m/z 297.1.

Example 11 Preparation of2-((1H-indazol-4-yl)methoxy)-5-methoxybenzaldehyde

Step 1

To a mixture of 4-(chloromethyl)-1H-indazole (1.0 g, 6.0 mol) in DCM (20mL) was added (Boc)₂O (1.96 g, 9.0 mmol) and DMAP (dimethylaminopyridine 67.2 mg, 0.6 mmol) at rt. The reaction mixture was stirred atrt for 1 h, concentrated, and purified on silica gel to give tert-butyl4-(chloromethyl)-1H-indazole-1-carboxylate (1.4 g, 88%) as an acolorless oil.

Step 2

A mixture of 2-hydroxy-5-methoxybenzaldehyde (46 mg, 0.3 mmol),tert-butyl 4-(chloromethyl)-1H-indazole-1-carboxylate (80 mg, 0.3 mmol),and K₂CO₃ (166 mg, 1.2 mmol) in DMF (1.0 mL) was heated at 80 OC for 2h. The mixture was filtered and the solid was washed with DCM. Thefiltrate was concentrated and purified on silica gel using a mixture ofEtOAc and hexanes as eluent to give tert-butyl4-((2-formyl-4-methoxyphenoxy)methyl)-1H-indazole-1-carboxylate (88 mg,77%) as a colorless oil.

Step 3

To tert-butyl4-((2-formyl-4-methoxyphenoxy)methyl)-1H-indazole-1-carboxylate (88 mg,0.23 mmol) in DCM (5.0 mL) was added TFA (2.0 mL). The mixture wasstirred at rt for 2 h and concentrated. The crude was purified on silicagel using a mixture of EtOAc and hexanes as eluent to give2-((1H-indazol-4-yl)methoxy)-5-methoxybenzaldehyde (50 mg, 77%) as awhite solid. ¹H NMR (400 MHz; CDCl₃) δ=10.53 (s, 1H), 8.23 (s, 1H), 7.54(d, 1H) 7.43 (t, 1H), 7.38 (d, 1H), 7.25 (d, 1H), 7.08-7.15 (m, 2H),5.51 (s, 2H), 3.82 (s, 3H). LRMS (M+H⁺) m/z 283.1.

Example 12 Preparation of3-(imidazo[1,2-a]pyridin-8-ylmethyl)-1,3-dihydroisobenzofuran-1-ol

Step 1

To a solution of methyl imidazo[1,2-a]pyridine-8-carboxylate (1.76 g, 10mmol) in toluene was added DIBAL (1M/THF, 20 ml) at −78° C. dropwise.The mixture was stirred at −78° C. for 1 h, quenched with MeOH (2 mL)and saturated NH₄Cl solution (50 mL) and warmed up to rt. The mixturewas continued to stir at rt for 1 h and diluted with DCM (60 mL). Theaqueous layer was extracted with DCM (60 mL) twice. The combined organiclayer was dried over MgSO₄ and concentrate. The residue was purified onsilica gel with 10% MeOH/DCM to giveimidazo[1,2-a]pyridine-8-carbaldehyde (0.8 g, 55%). LRMS (M+H⁺) m/z147.1.

Step 2

To a solution of sodium methoxide (5.4 M, 4.8 mL) in MeOH (20 mL) wasadded diethyl phosphite (3.31 g, 24 mmol) at 0° C. followed by additionof 2-formylbenzoic acid (3.0 g, 20 mmol) portion-wise over a period of20 min. The resulting mixture was warmed up to rt and continued to stirfor 2 h. Methanesulphonic acid (2.69 g, 28 mmol, 1.4 equiv.) was addedto the above mixture over a period of 30 min. The reaction mixture wasstirred for 30 min and concentrated to remove most of the MeOH. Theresidue was partitioned between DCM (100 mL) and water (50 mL). Theaqueous layer was extracted DCM twice. The combined organic layer wasdried over Na₂SO₄ and concentrated to give dimethyl3-oxo-1,3-dihydroisobenzofuran-1-ylphosphonate (4.6 g, 90%). LRMS (M+H⁺)m/z 257.1.

Step 3

To a solution of dimethyl 3-oxo-1,3-dihydroisobenzofuran-1-ylphosphonate(610 mg, 2.4 mmol), imidazo[1,2-a]pyridine-8-carbaldehyde (350 mg, 2.4mmol, 1 equiv.) in THF (5 mL) was added Et₃N (0.33 mL 2.4 mmol). Themixture was stirred at rt for 48 h. The precipitation was filtered offand washed with EtOAc. The filtrate was concentrated to give3-(imidazo[1,2-a]pyridin-8-ylmethylene)isobenzofuran-1(3H)-one (400 mg,64%) as a yellow solid. Small crude sample (˜20 mg) was purified onRP-HPLC with CH₃CN and water as eluent to separated the E/Z isomers (10mg, 7 mg). ¹H NMR (400 MHz, CD₃OD) Z-form: δ=8.52 (d, 1H), 7.95-7.91 (m,2H), 7.62-7.54 (m, 4H), 7.52-7.48 (m, 1H), 7.09 (s, 1H), 7.04 (t, 1H)E-form: δ=8.38 (d, 1H), 8.15 (d, H), 8.05 (d, 1H), 7.95 (d, 1H),7.90-7.84 (m, 2H), 7.67 (t, 1H), 7.64 (s, 1H), 7.33 (s, 1H), δ 7.05 (t,1H). LRMS (M+H⁺) m/z 263.1

Step 4

To a solution of3-(imidazo[1,2-a]pyridin-8-ylmethylene)isobenzofuran-1(3H)-one (180 mg,0.69 mmol) in EtOAc (12 mL) was added 10% Pd/C (110 mg). The mixture wasstirred under a hydrogen balloon overnight. The catalyst was filteredoff and the filtrate was concentrated and purified on silica gel with10% MeOH/DCM as eluent to give3-(imidazo[1,2-a]pyridin-8-ylmethyl)isobenzofuran-1(3H)-one (140 mg,78%). ¹H NMR (400 MHz, CD₃OD) δ=8.37 (d, 1H), δ 7.88 (s, 1H), 7.83 (d,1H), 7.74-7.63 (m, 2H), 7.60-7.53 (m, 2H), δ 7.22 (d, 1H), 6.86 (t, 1H),6.04 (dd, 1H), 3.76 (dd, 1H), 3.24 (dd, 1H).). LRMS (M+H⁺) m/z 265.1

Step 5

To a solution of3-(imidazo[1,2-a]pyridin-8-ylmethyl)isobenzofuran-1(3H)-one (80 mg, 0.3mmol) in DCM (6 mL) at −78° C., was added lithium triethyl borohydride(1M/THF, 0.3 mL) dropwise. The reaction mixture was stirred at −78 OCfor 30 min, diluted with DCM (\;10 mL), and quenched with MeOH (1 mL)and 5% HCl (2 mL). The mixture was warmed up to rt and stirred for 1 h.The solvents were removed and the residue was purified on RP-HPLC usingCH₃CN and water as eluent to give3-(imidazo[1,2-a]pyridin-8-ylmethyl)-1,3-dihydroisobenzofuran-1-ol (20mg, 25%). ¹H NMR (400 MHz, CD₃OD) δ=8.56 (t, 1H), 8.97 (d, 1H), 7.74 (s,1H), 7.45-7.32 (m, 5H), 7.07-7.00 (m, 1H), 6.38-6.30 (m, 1H), 5.84-5.80(m, 0.5H), 5.56 (dd, 0.5H), 3.69 (t, 0.5H), 3.65 (t, 0.5H), 3.26 (dd,0.5H), 3.13 (dd, 0.5H). LRMS (M+H⁺) m/z 267.1.

Example 13 Preparation of5-(imidazo[1,2-a]pyridin-8-ylmethoxy)-2-methoxybenzaldehyde

Step 1

To a mixture of 6-methoxyphen-3-ol (25 g, 0.2 mol) and K₂CO₃ (82.8 g,0.6 mol) in DMF (250 mL) is added bromomethyl methyl ether (30 g, 0.24mmol) slowly at rt for a period of 1 h. The reaction mixture is filteredand the filtrate is concentrated. The residue is purified on silica gelwith 25% EtOAc/hexanesas eluent to give2-methoxy-5-(methoxymethoxy)benzene.

Step 2

To a solution of 2-methoxy-5-(methoxymethoxy)benzene (20 g, 0.12 mol) inTHF is added diisopropylamine (0.24 g, 2.4 mmol). The solution is cooledto −40° C. followed by addition of MeLi (3M/THF, 72 mL, 0.216 mol)slowly. The resulting mixture is warmed to 0° C., stirred at 0° C. for 3h, cooled back down to −40° C. and added N-formylpiperidine (24 mL,0.216 mol). After stirring at −40° C. for 2 h, the mixture is quenchedwith a mixed solution of HCl (37%, 120 mL) and THF (250 mL). Thetemperature is then raised to rt and diluted with water (200 mL) andEtOAc (200 mL). The pH of the mixture is adjusted to 8-9 with solidK₂CO₃ and extracted with EtOAc (300 mL) twice. The organic layer iscombined, dried over Na₂SO₄, and concentrated. The residue is purifiedon silica gel with 25% EtOAc/hexanes as eluent to give2-methoxy-5-(methoxymethoxy)benzaldehyde.

Step 3

To a solution of 2-methoxy-5-(methoxymethoxy)benzaldehyde (10 g, 0.05mol) in THF (100 mL) was added 3 N HCl (150 mL). The reaction wasstirred at 50° C. for 30 min, cooled to rt, and diluted with water (100mL). The mixture was neutralized to pH 7-8 and extracted with EtOAc (200mL) three times. The organic layer was dried over Na₂SO₄ andconcentrated to give 5-hydroxy-2-methoxybenzaldehyde.

Step 4

A mixture of 5-hydroxy-2-methoxybenzaldehyde (723.6 mg, 4.7 mmol),8-(chloromethyl)-imidazol[1,2-a]pyridine (785 mg, 4.7 mmol), and K₂CO₃(1.9 g, 14.1 mmol) in DMF (20 mL) was heated at microwave reactor at125° C. for 15 min. The mixture was filtered and concentrated. Theresidue was purified on silica gel (50-100% EtOAc in hexanes) to give5-(imidazo[1,2-a]pyridin-8-ylmethoxy)-2-methoxybenzaldehyde.

The compounds Examples 14-16 were prepared according to the proceduredescribed in Example 13.

Example 14 Preparation of2-(imidazo[1,2-a]pyridin-2-ylmethoxy)-5-methoxybenzaldehyde (Compound5.)

¹H NMR (400 MHz, DMSO) δ 10.39 (s, 1H), 8.53 (d, J=6.8 Hz, 1H), 8.06 (s,1H), 7.54 (d, J=9.1 Hz, 1H), 7.42 (d, J=9.1 Hz, 1H), 7.29-7.22 (m, 2H),7.17 (d, J=3.3 Hz, 1H), 6.90 (t, J=6.8 Hz, 1H), 5.35 (s, 2H), 3.76 (s,3H).

Example 15 Preparation of 5-methoxy-2-(quinolin-5-ylmethoxy)benzaldehyde(Compound 10)

¹H NMR (400 MHz, CDCl₃) δ 9.09 (s, 1H), 7.73 (dd, J=4.0, 1.3 Hz, 1H),7.19 (d, J=8.4 Hz, 1H), 6.92 (d, J=8.4 Hz, 1H), 6.48 (t, J=8.4 Hz, 1H),6.40 (d, J=6.9 Hz, 1H), 6.24 (dd, J=8.5, 4.2 Hz, 1H), 6.10 (d, J=2.6 Hz,1H), 5.95-5.85 (m, 2H), 4.32 (s, 2H), 2.56 (s, 3H).

Example 16 Preparation of5-methoxy-2-((8-methylimidazo[1,2-a]pyridin-2-yl)methoxy)benzaldehyde(Compound 24)

¹H NMR (400 MHz, CD₃CN) δ 10.32 (s, 1H), 8.01 (d, J=6.8 Hz, 1H), 7.68(s, 1H), 7.19 (d, J=9.0 Hz, 1H), 7.13 (d, J=3.2 Hz, 1H), 7.08 (dd,J=9.0, 3.3 Hz, 1H), 6.90 (td, J=6.8, 1.2H 1H), 6.62 (t, J=6.s Hz, 1H),5.21 (s, 2H), 3.67 (s, 3H), 2.39 (s, 3H).

Example 17 Preparation of2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde(Compound 43)

A mixture of 2,6-dihydroxybenzaldehyde (1.96 g, 14.2 mmol, 2 eq.) andCs₂CO₃ (7.5 g, 21.3 mmol, 3 eq.) in DMF (180 mL) was stirred at rt for30 min. To this mixture was added3-(chloromethyl)-2-(1-isopropyl-1H-pyrazol-5-yl)pyridine hydrochloride(1.93 g, 7.1 mmol, 1 eq.) at rt. The mixture was continued to stir at rtO/N, filtered, concentrated and purified on silica gel using a mixtureof EtOAc and hexanes as eluent to give2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde(920 mg, 37%) as a pale yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 11.96 (s,1H), 10.40 (s, 1H), 8.77 (dd, J=4.8, 1.5 Hz, 1H), 8.00 (d, J=7.8 Hz,1H), 7.63 (d, J=1.8 Hz, 1H), 7.49-7.34 (m, 2H), 6.59 (d, J=8.5 Hz, 1H),6.37 (d, J=1.8 Hz, 1H), 6.29 (d, J=8.2 Hz, 1H), 5.10 (s, 2H), 4.67 (sep,J=6.7 Hz, 1H), 1.50 (d, J=6.6 Hz, 6H). LRMS (M+H⁺) m/z 338.1

Example 18 Preparation of2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde(Compound 43)

A mixture of 2,6-dihydroxybenzaldehyde (1.58 g, 11.47 mmol, 2 eq.) andK₂CO₃ (2.4 g, 17.22 mmol, 3 eq.) in DMF (150 mL) was stirred at rt for10 min. To this mixture was added3-(chloromethyl)-2-(1-isopropyl-1H-pyrazol-5-yl)pyridine hydrochloride(1.56 g, 5.74 mmol, 1 eq.) at rt. The mixture was heated at 50° C. for 2h, filtered, concentrated and purified on silica gel using a mixture ofEtOAc and hexanes as eluent to give2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde(1.71 g, 88%) as a pale yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 11.96(s, 1H), 10.40 (s, 1H), 8.77 (dd, J=4.8, 1.5 Hz, 1H), 8.00 (d, J=7.8 Hz,1H), 7.63 (d, J=1.8 Hz, 1H), 7.49-7.34 (m, 2H), 6.59 (d, J=8.5 Hz, 1H),6.37 (d, J=1.8 Hz, 1H), 6.29 (d, J=8.2 Hz, 1H), 5.10 (s, 2H), 4.67 (sep,J=6.7 Hz, 1H), 1.50 (d, J=6.6 Hz, 6H). LRMS (M+H⁺) m/z 338.1

Example 19 Preparation of5-((2-(2H-tetrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxybenzaldehyde Step1

To a mixture of 5-((2-bromopyridin-3-yl)methoxy)-2-methoxybenzaldehyde(100 mg, 0.31 mmol, 1 equiv), Zn(CN)₂ (71 mg, 0.62 mmol, 2.0 equiv),Pd(PPh₃)₄ (72 mg, 0.06 mmol, 0.2 equiv) in a 5 mL microwave tube isadded DMF (2 mL). The mixture is heated 15 min at 125° C. in a microwavereactor. The solid is filtered off and the filtrate is concentrated todryness. The crude was purified on silica gel using a mixture of EtOAcand hexanes as eluent to give3-((4-formyl-6-methoxyphen-3-yloxy)methyl)picolinonitrile.

Step 2

To TEA hydrochloride salt (123 mg, 0.89 mmol, 4 equiv.) and3-((4-formyl-6-methoxyphen-3-yloxy)methyl)picolinonitrile (70 mg, 0.26mmol, 1 equiv.) in chlorobenzene (5.0 mL) is added NaN₃ (48 mg, 0.89mmol, 4 equiv.) at rt. The mixture is heated to 110° C. for 2 h, cooledto rt, and added water (5.0 mL), The precipitate is filtered and washedwith EtOAc and water and dried under high vacuo to give5((2-(2H-tetrazol-5-yl)phen-3-yl)methoxy)-2-methoxyisonicotinaldehyde.

The compounds in Examples 20 and 21 were prepared according to theprocedure described in Example 19.

Example 20 Preparation of2-((3-(2H-tetrazol-5-ylbenzyl)oxy)-6-hydroxybenzaldehyde (Compound 44)

¹H NMR (400 MHz, CD₃CN) δ 11.95 (s, 1H), 10.45 (s, 1H), 8.17 (s, 1H),8.05 (d, J=7.7 Hz, 11), 7.69 (d, J=7.8 Hz, 1H), 7.62 (t, J=7.7 Hz, 1H),7.49 (t, J=: 8.4 Hz, 1H), 6.62 (d, J:=8.3 Hz, 1H), 6.54 (d, J=8.5 Hz,1H), 5.30 (s, 2H).

Example 21 Preparation of2-((4-(2H-tetrazol-5-yl)benzyl)oxy)-6-hydroxybenzaldehyde (Compound 45)

¹H NMR (400 MHz, DMSO) δ 11.77 (s, 1H), 10.40 (s, 1H), 8.06 (d, J=8.2Hz, 2H), 7.69 (d, J=8.0 Hz, 2H), 7.54 (t, J=8.4 Hz, 1H), 6.73 (d, J=8.4Hz, 1H), 6.56 (d, J=8.5 Hz, 1H), 5.33 (s, 2H).

Example 22 Preparation of5-((4-formyl-6-methoxyphen-3-yloxy)methyl)nicotinic acid Step 1

A mixture of 5-hydroxy-2-methoxybenzaldehyde (352 mg, 2.29 mmol, 1 eq.),methyl 5-(chloromethyl)nicotinate hydrochloride (506 mg, 2.29 mmol, 1eq.), and K₂CO₃ (1.26 g, 9.16 mmol, 4 eq.) in DMF (8.0 mL) is heated at60° C. for 3 h. The mixture is cooled and added into water (50 mL)dropwise. The precipitate is filtered, washed with water, and dried togive methyl 5-((4-formyl-6-methoxyphen-3-yloxy)methyl)nicotinate.

Step 2

To 5-((4-formyl-6-methoxyphen-3-yloxy)methyl)nicotinate (96 mg, 0.32mmol, 1 eq.) in a mixture of MeOH/THF (1/3, 8.0 mL) is added NaOH (3 N,1.7 mL, 5.1 mmol, 16 eq.). The mixture is stirred at rt for 2 h,acidified to pH 3, extracted with EtOAc (3×20 mL). The combined organiclayers are dried over Na₂SO₄ and concentrated to give5-((4-formyl-6-methoxypyridin-3-yloxy)methyl)nicotinic acid.

The compounds in Examples 23-25 were prepared according to the proceduredescribed in Example 22.

Example 23 Preparation of methyl 4-((2-formylphenoxy)methyl)benzoate(Compound 46)

¹H NMR (400 MHz, CDCl₃) δ 10.51 (s, 1H), 8.01 (d, J=8.3 Hz, 2H), 7.81(dd, J=7.7, 1.8 Hz, 1H), 7.51-7.40 (m, 3H), 7.00 (t, J=7.5 Hz, 1H), 6.94(d, J=8.4 Hz, 1H), 5.19 (s, 2H), 3.86 (s, 3H).

Example 24 Preparation of 4-((2-formylphenoxy)methyl)benzoic acid(Compound 47)

¹H NMR (400 MHz, CDCl₃) δ 10.52 (s, 1H), 8.09 (d, J=8.2 Hz, 2H), 7.81(dd, J=7.7, 1.6 Hz, 1H), 7.53-7.43 (m, 3H), 7.01 (t, J=7.5 Hz, 1H), 6.95(d, J=8.4 Hz, 1H), 5.21 (s, 2H).

Example 25 Preparation of methyl 3-((2-formylphenoxy)methyl)benzoate(Compound 48)

¹H NMR (400 MHz, CDCl₃) δ 10.58 (s, 1H), 8.14 (s, 1H), 8.06 (d, J=7.8Hz, 1H), 7.90 (dd, J=7.7, 1.8 Hz, 1H), 7.69 (d, J=7.7 Hz, 1H), 7.60-7.48(m, 2H), 7.08 (dd, J=14.4, 7.9 Hz, 2H), 5.26 (s, 2H), 3.96 (s, 3H).

Example 26 Preparation of 5-hydroxy-2-methoxybenzaldehyde Step 1

To a solution of 6-methoxyphen-3-ol (20 g, 0.16 mol, 1 eq.) in DMF (200mL) was added NaH (60% in mineral oil; 9.6 g, 0.24 mol, 1.5 eq.) at 0-5°C. portion-wise. Upon the completion of addition, the mixture wascontinued to stir at 0-5° C. for 15 min, added chloromethyl methyl ether(15.5 g, 0.19 mol, 1.2 eq.), stirred at 0-5° C. for another 20 min, andquenched with NH₄Cl_((sat)) solution. The aqueous layer was extractedwith EtOAc (3×100 mL) and the combined organic layers were washed withwater and brine, dried over Na₂SO₄, concentrated, and purified on silicagel using 25% EtOAc/hexanes as eluent to give2-methoxy-5-(methoxymethoxy)benzene (24.1 g, 89.3%) as a colorless oil.

Step 2

To a mixture of 2-methoxy-5-(methoxymethoxy)benzene (30 g, 0.178 mol, 1eq.) and diisopropylamine (507 uL, 3.6 mmol, 0.02 eq.) in THF (500 mL)was added methyl lithium (1.6 M/THF, 200 mL, 0.32 mol, 1.8 eq.) at −40°C. Upon the completion of addition, the mixture was warmed to 0° C.,continued to stir at 0° C. for 3 h, cooled back down to −40° C. andadded DMF (24.7 mL, 0.32 mol, 1.8 eq.) slowly. The mixture was thenstirred at −40° C. for 1 h, quenched with a mixture of HCl (12 N, 120mL) and THF (280 mL), warmed to rt, and added water (200 mL). The pH ofthe mixture was adjusted to pH 8-9 with solid K₂CO₃. The aqueous layerwas extracted with EtOAc (300 mL) twice. The combined organic layerswere dried over Na₂SO₄ and concentrated to give2-methoxy-5-(methoxymethoxy)benzaldehyde (33.5 g, 95.7%) as a brownsolid, which was used for next step without further purification. ¹H NMR(400 MHz; CD₃OD) 7.90 (s, 1H), 6.92 (s, 1H), 5.64 (s, 1H), 5.20 (s, 2H),3.84 (s, 3H), 3.48 (s, 3H). LRMS (M+H⁺) m/z 198.1

Step 3

To a solution of 2-methoxy-5-(methoxymethoxy)benzaldehyde (33.5 g, 0.17mol, 1 eq.) in THF (150 mL) was added HCl (3 N, 250 mL, 4.4 eq.). Thereaction was stirred at 50° C. for 1 h, cooled to rt, and diluted withwater (500 mL). The mixture was neutralized to pH 7-8 with solid K₂CO₃.The pale yellow solid was collected, washed with water, and dried togive 5-hydroxy-2-methoxybenzaldehyde (17.9 g, 74.6%) as a pale yellowsolid. ¹H NMR (400 MHz; DMSO) δ=10.31 (s, 1H), 8.03 (s, 1H), 6.89 (s,1H), 3.80 (s, 3H). LRMS (M+H⁺) m/z 154.0.

Example 27 Preparation of5-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxybenzaldehyde(Compound 150) Step 1

To a solution of 2-bromonicotinic acid (4.0 g, 20 mmol) andtriethylamine (3.34 mL, 24 mmol, 1.2 eq.) in THF (100 mL) was addedi-butyl chloroformate (3.12 mL, 24 mmol, 1.2 eq.) at 0° C. The mixturewas stirred at 0° C. for 10 min and filtered. To this filtrate was addeda suspension of NaBH₄ (1.52 g, 40 mmol, 2 eq.) in water (1.0 mL) at 0°C. The mixture was stirred for 30 min, added water (3 mL), continued tostir for 2 h, and concentrated to dryness. The crude was purified onsilica gel using a mixture of ethylacetate and hexanes as eluent to give(2-bromopyridin-3-yl)methanol (3.4 g, 90%) as a white solid. LRMS (M+H⁺)m/z 188.0.

Step 2

To a mixture of (2-bromopyridin-3-yl)methanol (20.0 g, 106.4 mmol, 1eq.) and imidazole (14.5 g, 212.8 mmol, 2 eq.) in DMF (50.0 mL) wasadded TBSCl (19.2 g, 150.7 mmol, 1.2 eq.) at rt. The mixture was stirredat rt for 1 h and diluted with a mixture of water (100 mL) and EtOAc(300 mL). The organic layer was washed with NH₄Cl_((sat)) solution andbrine, dried over Na₂SO₄, concentrated, and purified on silica gel using10% EtOAc/hexanes as eluent to give2-bromo-3-((tert-butyldimethylsilyloxy)methyl)pyridine (30.1 g, 94%) asa colorless oil. LRMS (M+H⁺) m/z 302.0.

Step 3

A mixture of 2-bromo-3-((tert-butyldimethylsilyloxy)methyl)pyridine(30.1 g, 100.0 mmol, 1 eq.) and Zn(CN)₂ (23.5 g, 200.0 mmol, 2.0 eq.) inDMF (100.0 mL) was purged with N₂ for 5 min and added Pd(PPh₃)₄(5.78 g,5.0 mmol, 0.05 eq.). The mixture was heated at 120° C. for 2 h under N₂,cooled, filtered, concentrated, and purified on silica gel using amixture of EtOAc and hexanes as eluent to give3-((tert-butyldimethylsilyloxy)methyl)picolinonitrile (20.4 g, 82%) as acolorless oil. LRMS (M+H⁺) m/z 249.1.

Step 4

Methylmagnesium bromide (3M/ether, 41.0 mL, 123.4 mmol) was added to astirred solution of3-((tert-butyldimethylsilyloxy)methyl)picolinonitrile (20.4 g, 82.25mmol) in THF (100.0 mL) at −78° C. The reaction mixture was warm to rt,quenched with aqueous citric acid solution, and extracted with EtOAc (50mL) twice. The combined organic layers were washed with NaHCO_(3 (sat))solution and brine, dried over Na₂SO₄, concentrated, and purified onsilica gel using a mixture of EtOAc/hexanes as eluent to give1-(3-((tert-butyldimethylsilyloxy)methyl)pyridin-2-yl)ethanone (12.9 g,59%) as a colorless oil. LRMS (M+H⁺) m/z 266.2.

Step 5

1-(3-((tert-butyldimethylsilyloxy)methyl)pyridin-2-yl)ethanone (10.8 g,40.75 mmol) in dimethoxy-N,N-dimethylmethanamine (15.0 mL) was heated toreflux for 3 days. The mixture was concentrated and used for next stepwithout further purification. LRMS (M+H⁺) m/z 321.1.

Step 6

To(E)-1-(3-((tert-butyldimethylsilyloxy)methyl)pyridin-2-yl)-3-(dimethylamino)prop-2-en-1-one(crude, 1.03 g, 3.22 mmol, 1 eq.) in EtOH (10 mL) was addedisopropylhydrazine hydrochloride (430 mg, 3.86 mmol, 1.2 eq.). Themixture was heated at 80° C. for 2 h, cooled, added HCl (6 N, 0.5 mL),and stirred O/N. The mixture was concentrated and diluted with EtOAc (80mL) and NaHCO_(3(sat)) (10 mL) solution. The layers were separated andthe aqueous layer was extracted with EtOAc three times. The combinedorganic layers were dried over Na₂SO₄, concentrated, and purified onsilica gel using EtOAc as eluent to give(2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methanol (500 mg, 71%) and(2-(1-isopropyl-1H-pyrazol-3-yl)pyridin-5-yl)methanol (55 mg, 25%) aspale yellow oils. Data for2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methanol: ¹H NMR (400 MHz,CDCl₃) δ 8.67 (dd, J=4.7, 1.5 Hz, 1H), 8.0 (d, J=7.8 Hz, 1H), 7.61 (d,J=1.8 Hz, 1H), 7.39 (dd, J=7.8, 4.8 Hz, 1H), 6.37 (d, J=1.8 Hz, 1H),4.67 (s, 2H), 4.55 (sep, J=6.6 Hz 1H), 1.98-2.05 (br, 1H), 1.47 (d,J=6.6 Hz, 6H). LRMS (M+H⁺) m/z 218.1 Data for(2-(1-isopropyl-1H-pyrazol-3-yl)pyridin-5-yl)methanol: ¹H NMR (400 MHz,CDCl₃) δ 8.62 (dd, J=4.8, 1.6 Hz, 1H), 7.72 (d, J=7.6 Hz, 1H), 7.55 (d,J=2.4 Hz, 1H), 7.23 (dd, J=7.6, 4.8 Hz, 1H), 6.99 (dd, J=8.0, 6.5 Hz,1H), 6.07 (t, J=7.6 Hz, 1H), 4.67 (d, J=7.6 Hz, 2H), 4.58 (sep, J=6.7Hz, 1H), 1.60 (d, J=6.7 Hz, 1H). LRMS (M+H⁺) m/z 218.1.

Step 7

To (2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methanol (560 mg, 2.58mmol) in DCM (10 mL) was added SOCl₂ (3.0 mL) at rt. The reactionmixture was stirred at rt for 4 h and concentrated to dryness. The crudesolid was suspended in toluene and concentrated to dryness. The processwas repeated three times and dried under vacuum to give3-(chloromethyl)-2-(1-isopropyl-1H-pyrazol-5-yl)pyridine hydrochloride(700 mg) as an off-white solid, which was used for next step withoutfurther purification.

Step 8

A mixture of 5-hydroxy-2-methoxybenzaldehyde (395 mg, 2.58 mmol, 1 eq.),3-(chloromethyl)-2-(1-isopropyl-1H-pyrazol-5-yl)pyridine hydrochloride(700 mg, 2.58 mmol, 1 eq.), and K₂CO₃ (1.4 g, 10.32 mmol, 4 eq.) in DMF(10.0 mL) was heated at 70° C. for 2 h. The mixture was cooled,filtered, concentrated, and purified on silica gel using a mixture ofEtOAc and hexanes as eluent to give5-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxybenzaldehyde(590 mg, 65%) as an off-white solid.

Step 9

5-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxybenzaldehyde(980 mg, 2.78 mmol, 1 eq.) in HCl (6 N, 9.2 mL, 20 eq.) solution wasfrozen at −78° C. The mixture was lyophilized O/N to give5-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxybenzaldehydeas a yellow solid.

Example 28 Preparation of2-bromo-3-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde(Compound 49)

The title compound was prepared according to the procedure described inExample 27.

¹H NMR (400 MHz, CDCl₃) δ 10.46 (s, 2H), 8.77 (d, J=4.6 Hz, 2H), 8.22(d, J=7.9 Hz, 2H), 7.64 (s, 2H), 7.59 (d, J=7.8 Hz, 2H), 7.47 (dd,J=8.0, 4.8 Hz, 2H), 7.37 (t, J=7.9 Hz, 2H), 7.04 (d, J=8.1 Hz, 2H), 6.43(d, J=1.0 Hz, 2H), 5.11 (s, 4H), 4.67 (sep, J=6.6 Hz, 3H), 1.50 (d,J=6.6 Hz, 11H).

Example 29 Preparation of 2-hydroxy-6-((2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde(Compound 50) Step 1

To (3,3,3-trifluoroethyl)hydrazine (25 g, 50% wt in water, 153.5 mmol, 1eq.) in a RB flask (250 mL) was added HCl (12 N, 25.6 mL, 307.0 mmol, 2eq.). The mixture was concentrated to give(3,3,3-trifluoroethyl)hydrazine dihydrochloride (1.07 g) as a yellowsolid. LRMS (M+H) m/z 129.1.

Step 2

To(E)-1-(3-((tert-butyldimethylsilyloxy)methyl)pyridin-2-yl)-3-(dimethylamino)prop-2-cn-1-one(crude above, 5.91 g, 18.44 mmol, 1 eq.) in EtOH (20 mL) was added(3,3,3-trifluoroethyl)hydrazine dihydrochloride (4.13 g, crude above,22.13 mmol, 1.2 eq.) at rt. The mixture was heated at 80° C. for 1 h,concentrated, and diluted with EtOAc (50 mL) and NaHCO_(3(sat)) solution(10 mL). The layers were separated and aqueous layer was extracted withEtOAc three times. The combined organic layers were dried over Na₂SO₄,concentrated, and purified on silica gel using a mixture of EtOAc andhexanes as eluent to give3-((tert-butyldimethylsilyloxy)methyl)-2-(1-(3,3,3-trifluoroethyl)-1H-pyrazol-5-yl)pyridine(5.90 g; 86% for 2 steps). LRMS (M+H⁺) m/z 372.2.

Step 3

To3-((tert-butyldimethylsilyloxy)methyl)-2-(1-(3,3,3-trifluoroethyl)-1H-pyrazol-5-yl)pyridine(5.91 g, 15.93 mmol) in MeOH (20 mL) was added HCl (4 N, 8.0 mL). Themixture was stirred at rt for 1 h, concentrated, and diluted with EtOAc(50 mL) and NaHCO_(3(sat)) solution (10 mL). The layers were separatedand aqueous layer was extracted with EtOAc three times. The combinedorganic layers were dried over Na₂SO₄, and concentrated to give(2-(1-(3,3,3-trifluoroethyl)-1H-pyrazol-5-yl)pyridin-3-yl)methanol (4.1g, quantitative yield) as colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 8.54(dd, J=4.7, 1.5 Hz, 1H), 7.92 (dd, J=7.9, 1.2 Hz, 1H), 7.57 (d, J=1.9Hz, 1H), 7.30 (dd, J=7.8, 4.8 Hz, 1H), 6.50 (d, J=1.9 Hz, 1H), 5.09 (q,J=8.6 Hz, 2H), 4.63 (s, 2H), 1.76 (s, 1H). LRMS (M+H⁺) m/z 272.1

Step 4

To (2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)pyridin-3-yl)methanol(408 mg, 1.59 mmol) in DCM (5 mL) was added SOCl₂ (1.5 mL) at rt. Thereaction mixture was stirred at rt for 4 h and concentrated to dryness.The crude solid was suspended in toluene and concentrated to dryness.The process was repeated three times and dried under vacuum to give3-(chloromethyl)-2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)pyridinehydrochloride (498 mg) as an off-white solid, which was used for nextstep without further purification.

Step 5

A mixture of 2,6-dihydroxybenzaldehyde (438 mg, 11.47 mmol, 2 eq.) andK₂CO₃ (2.4 g, 17.22 mmol, 3 eq.) in DMF (150 mL) was stirred at rt for10 min. To this mixture was added3-(chloromethyl)-2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)pyridinehydrochloride (498 mg, 1.59 mmol, 1 eq.) at rt. The mixture was heatedat 50° C. for 2 h, filtered, concentrated and purified on silica gelusing a mixture of EtOAc and hexanes as eluent to2-hydroxy-6-((2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde(338.4 mg, 56%) as a pale yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 11.99(s, 1H), 10.41 (s, 1H), 8.76 (dd, J=4.7, 1.6 Hz, 1H), 8.01 (dd, J=7.9,1.4 Hz, 1H), 7.69 (d, J=1.9 Hz, 1H), 7.49-7.39 (m, 2H), 6.61 (d, J=8.5Hz, 1H), 6.53 (d, J=1.9 Hz, 1H), 6.32 (d, J=8.3 Hz, 1H), 5.30 (q, J=8.6Hz, 2H), 5.17 (s, 2H). LRMS (M+H⁺) m/z 378.1

Example 30 Preparation of 2-hydroxy-6-((2-(1-(3, 3,3-trifluoropropyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde(Compound 51) Step 1

To a mixture of benzyl hydrazinecarboxylate (5.0 g, 30.3 mmol, 1 eq.)and DIEA (15.0 mL, 90.9 mmol, 3 eq.) in DMF (20 mL) was added3,3,3-trifluoropropyl bromide (10.7 g 60.6 mmol, 2 eq.) at rt. Themixture was heated at 80° C. for 20 h, concentrated, and purified onsilica gel using a mixture of EtOAc and hexanes as eluent to benzyl2-(3,3,3-trifluoropropyl)hydrazinecarboxylate (4.2 g; 53%) as a whitesolid. ¹H NMR (400 MHz, CDCl₃) δ 7.33-7.17 (m, 5H), 6.11 (s, 1H), 5.01(s, 2H), 4.00 (s, 1H), 3.00 (dd, J-12.2, 7.1 Hz, 2H), 2.17 (qt, J=10.8,7.3 Hz, 2H). LRMS (M+H⁺) m/z 263.1

Step 2

To benzyl 2-(3,3,3-trifluoropropyl)hydrazinecarboxylate (1.7 g, 6.49mmol, 1 eq.) in a mixture of EtOH (30 mL) were added Pd/C (1.0 g) andHCl (12 N, 2.0 mL). The mixture was charged with H₂ (60 psi), stirred atrt for 1 h, filtered, and concentrated to give(3,3,3-trifluoropropyl)hydrazine dihydrochloride (1.07 g) as a yellowsolid. LRMS (M+H) m/z 129.1.

Step 3

To(E)-1-(3-((tert-butyldimethylsilyloxy)methyl)pyridin-2-yl)-3-(dimethylamino)prop-2-en-1-one(crude above, 1.73 g, 5.41 mmol, 1 eq.) in EtOH (10 mL) was added(3,3,3-trifluoropropyl)hydrazine dihydrochloride (1.30 g, crude above,6.49 mmol, 1.2 eq.) at rt. The mixture was heated at 80° C. for 1 h,concentrated, and diluted with EtOAc (50 mL) and NaHCO_(3(sat)) solution(10 mL). The layers were separated and aqueous layer was extracted withEtOAc three times. The combined organic layers were dried over Na₂SO₄,concentrated, and purified on silica gel using a mixture of EtOAc andhexanes as eluent to give3-((tert-butyldimethylsilyloxy)methyl)-2-(1-(3,3,3-trifluoropropyl)-1H-pyrazol-5-yl)pyridine(1.58 g; 76% for 2 steps). ¹H NMR (400 MHz, CDCl₃) δ 8.53 (dd, J=4.7,1.6 Hz, 1H), 7.96-7.88 (m, 1H), 7.51 (d, J=1.9 Hz, 1H), 7.29 (dd, J=7.9,4.7 Hz, 1H), 6.34 (d, J=1.9 Hz, 1H), 4.62 (s, 2H), 4.45-4.33 (m, 2H),2.82-2.61 (m, 2H), 0.85 (s, 8H), −0.00 (s, 5H). LRMS (M+H⁺) m/z 386.2.

Step 4

To3-((tert-butyldimethylsilyloxy)methyl)-2-(1-(3,3,3-trifluoropropyl)-1H-pyrazol-5-yl)pyridine(1.58 g, 4.1 mmol) in MeOH (20 mL) was added HCl (4 N, 4.0 mL). Themixture was stirred at rt for 1 h, concentrated, and diluted with EtOAc(50 mL) and NaHCO_(3(sat)) solution (10 mL). The layers were separatedand aqueous layer was extracted with EtOAc three times. The combinedorganic layers were dried over Na₂SO₄, and concentrated to give(2-(1-(3,3,3-trifluoropropyl)-1H-pyrazol-5-yl)pyridin-3-yl)methanol (1.1g, 99%) as colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 8.64 (dd, J=4.7, 1.7Hz, 1H), 8.00 (dd, J=7.9, 1.7 Hz, 1H), 7.57 (d, J=1.9 Hz, 1H), 7.38 (dd,J=7.9, 4.8 Hz, 1H), 6.48 (d, J=1.9 Hz, 1H), 4.69 (s, 2H), 4.51-4.43 (m,2H), 2.85-2.72 (m, 2H), 2.70 (s, 1H). LRMS (M+H⁺) m/z 272.1.

Step 5

To (2-(1-(2,2,2-trifluoropropyl)-1H-pyrazol-5-yl)pyridin-3-yl)methanol(140 mg, 0.52 mmol) in DCM (5 mL) was added SOCl₂ (2.0 mL) at rt. Thereaction mixture was stirred at rt for 4 h and concentrated to dryness.The crude solid was suspended in toluene and concentrated to dryness.The process was repeated three times and dried under vacuum to give3-(chloromethyl)-2-(1-(2,2,2-trifluoropropyl)-1H-pyrazol-5-yl)pyridinehydrochloride (498 mg) as an off-white solid, which was used for nextstep without further purification.

Step 6

A mixture of 2,6-dihydroxybenzaldehyde (144 mg, 1.04 mmol, 2 eq.) andK₂CO₃ (214 mg, 1.56 mmol, 3 eq.) in DMF (20 mL) was stirred at rt for 10min. To this mixture was added3-(chloromethyl)-2-(1-(2,2,2-trifluoropropyl)-1H-pyrazol-5-yl)pyridinehydrochloride (168 mg, 0.52 mmol, 1 eq.) at rt. The mixture was heatedat 50° C. for 2 h, filtered, concentrated and on RP-HPLC (Gemini21.2×150 mm) using a mixture of CH₃CN and water as eluent to give2-hydroxy-6-((2-(1-(3,3,3-trifluoropropyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde(53.5 mg, 26%) as an off-white solid. ¹H NMR (400 MHz, CDCl₃) δ 11.98(s, 1H), 10.38 (s, 1H), 8.77 (dd, J=4.7, 1.6 Hz, 1H), 8.01 (dd, J=7.9,1.6 Hz, 1H), 7.61 (d, J=1.9 Hz, 1H), 7.49-7.39 (m, 2H), 6.61 (d, J=8.5Hz, 1H), 6.44 (d, J=1.9 Hz, 1H), 6.34 (d, J=8.2 Hz, 1H), 5.15 (s, 2H),4.56 (dd, J=8.3, 6.7 Hz, 2H), 3.02-2.72 (m, 2H). LRMS (M+H⁺) m/z 392.1.

Example 31 Preparation of Benzaldehyde Derivatives

Compounds 52-55 were prepared according to the methods described above.

2-Fluoro-6-((2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde(Compound 52). ¹H NMR (400 MHz, CDCl₃) δ 10.51 (s, 1H), 8.74 (dd, J=4.7,1.6 Hz, 1H), 8.21 (dd, J=7.9, 1.6 Hz, 1H), 7.70 (d, J=1.9 Hz, 1H),7.54-7.41 (m, 2H), 6.82 (dd, J=10.0, 8.6 Hz, 1H), 6.70 (d, J=8.5 Hz,1H), 6.56 (d, J=1.9 Hz, 1H), 5.28 (q, J=8.6 Hz, 2H), 5.20 (s, 2H).

2-Fluoro-6-((2-(1-(3,3,3-trifluoropropyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde(Compound 53). ¹H NMR (400 MHz, CDCl₃) δ 10.50 (s, 1H), 8.75 (dd, J=4.7,1.6 Hz, 1H), 8.22 (dd, J=7.9, 1.6 Hz, 1H), 7.62 (d, J=1.9 Hz, 1H),7.54-7.42 (m, 2H), 6.83 (dd, J=10.0, 8.7 Hz, 1H), 6.73 (d, J=8.5 Hz,1H), 6.46 (d, J=1.9 Hz, 1H), 5.19 (s, 2H), 4.59-4.51 (m, 2H), 2.96-2.76(m, 2H).

2-Fluoro-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde(Compound 54). ¹H NMR (400 MHz, CDCl₃) δ 10.41 (s, 1H), 8.66 (dd, J=4.7,1.6 Hz, 1H), 8.13 (dd, J=7.9, 1.4 Hz, 1H), 7.55 (d, J=1.8 Hz, 1H),7.46-7.29 (m, 2H), 6.72 (dd, J=10.0, 8.7 Hz, 1H), 6.59 (d, J=8.5 Hz,1H), 6.29 (d, J=1.8 Hz, 1H), 5.03 (s, 2H), 4.56 (sep, J=6.7 Hz, 1H),1.40 (d, J=6.6 Hz, 6H).

Example 32 Preparation of1-(2-formyl-3-hydroxyphenethyl)piperidine-4-carboxylic acid (Compound55)

To a solution of 2-bromo-6-hydroxybenzaldehyde (3.8 g, 18.91 mmol, 1eq.) in a mixture of THF and MeOH (4/1, 25 mL) was added NaBH₄ (1.4 g,37.81 mmol, 1.5 eq.) at rt portion-wise. Upon the completion ofaddition, the mixture was continued to stir at rt for 30 min. Themixture was quenched with HCl (4 N) and extracted with EtOAC twice. Thecombined organic layer was dried over Na₂SO₄, concentrated, and purifiedon silica gel using 25% EtOAc/hexanes as eluent to give3-bromo-2-(hydroxymethyl)phenol (2.3 g, 60%) as a colorless oil.

To 3-bromo-2-(hydroxymethyl)phenol (2.3 g, 11.3 mmol, 1 eq.) in acetone(20.0 mL) were added 2,2-dimethoxypropane (6.0 mL), PTSA (215 mg, 1.13mmol, 0.1 eq.), and Na₂SO₄ (5.0 g). The mixture was heated at 40° C.O/N, cooled to rt, and diluted with EtOAc.

The organic layer was washed with NaHCO_(3(sat)) solution and brine,dried over Na₂SO₄, concentrated, and purified on silica gel using amixture of EtOAc and hexanes to give5-bromo-2,2-dimethyl-4H-benzo[d][1,3]dioxine (2.1 g, 76%) as a colorlessoil. ¹H NMR (400 MHz, CDCl₃) δ 7.13 (dd, J=8.0, 1.2 Hz, 1H), 7.07 (t,J=8.0 Hz, 1H), 6.81 (dd, J=8.0, 1.2 Hz, 1H), 4.77 (s, 2H), 1.56 (s, 6H).

To a mixture of 5-bromo-2,2-dimethyl-4H-benzo[d][1,3]dioxine (2.1 g,8.64 mmol, 1 eq.), Pd₂(dba)₃ (400 mg, 0.43 mmol, 0.05 eq.), Q-Phos (460mg, 0.65 mmol, 0.075 mmol) in THF (100 mL) purged with N₂ for 10 min wasadded ZnCl(CH₂CO₂Bu) (0.5 M/ether, 35 mL, 17.38 mmol, 2 eq.). Themixture was heated at 50° C. for 16 h, cooled to rt, added NH₄C₁(sat)solution, and diluted with EtOAc. The organic layer was separated, driedover Na₂SO₄, concentrated, and purified on silica gel using a mixture ofEtOAc and hexanes to give tert-butyl2-(2,2-dimethyl-4H-benzo[d][1,3]dioxin-5-yl)acetate (2.6 g, 80% pure,87%) as a brown oil. ¹H NMR (400 MHz, CDCl₃) δ 7.06 (t, J=7.9 Hz, 1H),6.73 (d, J=7.4 Hz, 1H), 6.68 (d, J=8.2 Hz, 1H), 4.78 (s, 2H), 1.47 (s,6H), 1.36 (s, 9H).

To a solution of tert-butyl2-(2,2-dimethyl-4H-benzo[d][1,3]dioxin-5-yl)acetate (2.6 g, 80% pure,9.34 mmol, 1 eq.) in THF (20 mL) were added LiBH₄ (7.0 mL, 14.01 mmol,1.5 eq.) and MeOH (1.0 mL) at rt. The mixture was stirred at rt for 30min, added MeOH (20 mL), concentrated to dryness, added MeOH (20 mL) andsilica gel, and concentrated to dryness again. The mixture was loadeddirectly on silica gel for purification using a mixture of EtOAc andhexanes as eluent to give2-(2,2-dimethyl-4H-benzo[d][1,3]dioxin-5-yl)ethanol (1.1 g, 71%) as apale brown oil. ¹H NMR (400 MHz, CDCl₃) δ 7.28 (t, J=7.9 Hz, 1H), 6.92(d, J=7.4 Hz, 1H), 6.86 (d, J=8.2 Hz, 1H), 5.02 (s, 2H), 3.99 (q, J=6.4Hz, 2H), 2.86 (t, J=6.6 Hz, 2H), 1.68 (s, 6H), 1.57 (t, J=5.5 Hz, 1H).

To a solution of 2-(2,2-dimethyl-4H-benzo[d][1,3]dioxin-5-yl)ethanol(400 mg, 1.92 mmol, 1 eq.) in THF (20 mL) were added MsCl (438 mg, 3.84mmol, 2.0 eq.) and TEA (0.8 mL, 5.76 mmol, 3.0 eq.) at rt. The mixturewas stirred at rt for 1 h and diluted with EtOAc. The organic layer waswashed with water and brine, dried over Na₂SO₄, and concentrated to give2-(2,2-dimethyl-4H-benzo[d][1,3]dioxin-5-yl)ethyl methanesulfonate (400mg, crude) as a pale brown oil, which was used for next step withoutpurification.

To 2-(2,2-dimethyl-4H-benzo[d][1,3]dioxin-5-yl)ethyl methanesulfonate(176 mg, 0.59 mmol, crude above, 1 eq.) in DMF (1.0 mL) was added ethylpiperidine-4-carboxylate (186 mg, 1.18 mmol, 2.0 eq.) at rt. The mixturewas stirred at 60° C. for 2 h, cooled to rt, and purified on RP-HPLC(Gemini 21.2 mm×150 mm) using a mixture of CH₃CN and water (0.1% HCOOH)as eluent to give ethyl1-(2-(2,2-dimethyl-4H-benzo[d][1,3]dioxin-5-yl)ethyl)piperidine-4-carboxylate(100 mg, 49% for two steps). ¹H NMR (400 MHz, CDCl₃) δ 8.45 (s, 1H),7.13 (t, J=7.9 Hz, 1H), 6.73 (d, J=7.9 Hz, 2H), 4.86 (s, 2H), 4.19 (q,J=7.1 Hz, 2H), 3.22 (s, 2H), 3.09-2.95 (m, 1H), 2.95-2.79 (m, 4H), 2.76(s, 1H), 2.66-2.48 (m, 1H), 2.23-1.99 (m, 4H), 1.55 (s, 6H), 1.29 (t,J=7.1 Hz, 3H). LRMS (M+H⁺) m/z 348.1.

To ethyl1-(2-(2,2-dimethyl-4H-benzo[d][1,3]dioxin-5-yl)ethyl)piperidine-4-carboxylate(100 mg, 0.49 mmol, 1 eq.) in THF (10 mL) were added HCl (6 N, 10 drops)and water (1.0 mL) at rt. The mixture was stirred at 60° C. for 2 h,cooled, and basified with NaHCO_(3(sat)) solution. The mixture wasfiltered and concentrated. The residue was bring into THF (10 mL) andfiltered. The filtrate was concentrated to give ethyl1-(3-hydroxy-2-(hydroxymethyl)phenethyl)piperidine-4-carboxylate (85 mg,crude) as a pale brown oil, which was used for next step withoutpurification. LRMS (M+H⁺) m/z 308.1.

To ethyl1-(3-hydroxy-2-(hydroxymethyl)phenethyl)piperidine-4-carboxylate (85 mg,crude above) in THF (20.0 mL) was added MnO₂ (500 mg, 5.75 mmol) at rt.The mixture was stirred at rt for 1 h, filtered, and concentrated togive ethyl 1-(2-formyl-3-hydroxyphenethyl)piperidine-4-carboxylate (80mg, crude) as a pale brown solid, which was used for next step withpurification. LRMS (M+H⁺) m/z 306.1.

To ethyl 1-(2-formyl-3-hydroxyphenethyl)piperidine-4-carboxylate (80 mg,crude above) in THF (5.0 mL) was added NaOH (3 N, 1.0 mL). The mixturewas stirred at rt for 2 h and acidified to pH 3-4 using HCl (2 N). Themixture was concentrated and purified on RP-HPLC (Gemini 21.2 mm×150 mm)using a mixture of CH₃CN and water (0.1% HCOOH) as eluent to give1-(2-formyl-3-hydroxyphenethyl)piperidine-4-carboxylic acid (40 mg, 29%for three steps) as a yellow solid. ¹H NMR (400 MHz, DMSO) δ 10.26 (s,1H), 8.65 (s, 2H), 6.91 (dd, J=8.7, 6.9 Hz, 1H), 6.16 (d, J=7.9 Hz, 1H),5.76 (d, J=6.7 Hz, 1H), 3.01-2.89 (m, 4H), 2.50-2.36 (m, 2H), 2.03 (t,J=10.3 Hz, 2H), 1.92-1.76 (m, 3H), 1.69-1.49 (m, 2H). LRMS (M+H⁺) m/z278.4. ¹H NMR (400 MHz, DMSO-d6) δ 10.1 (s, 1H), 8.55 (s, 2H), 6.75 (dd,J=Hz, 1H), 6.05 (d, J=Hz, 1H), 5.6 (d, J=Hz, 1H), 2.7 (m, 4H), 2.3 (m,2H), 1.85 (m, 2H), 1.7 (m, 3H), 1.5 (m, 2H).

In Vitro Testing Example 33 Modulation of Hemoglobin Oxygen Affinity bySubstituted Benzaldehyde Compounds—Assay Procedure

Oxygen equilibrium curves (OEC) in purified Hemoglobin S (HbS) weremeasured by the change in p50, the partial pressure of oxygen at whichthe heme binding sites in the HbS sample are 50% saturated with oxygen.HbS was purified by a modified procedure (Antonini and Brunori, 1971;Heomoglobin and Myoglobin in their Reactions with Ligands; North HollandPublishing Company; Amsterdam, London) from blood obtained fromhomozygous sickle cell patients though the Hemoglobinopathy Center atChildren's Hospital Oakland Research Institute (CHORI) withInstitutional Review Board approval. Oxygen equilibrium curves werecarried out with a HEMOX analyzer, (TCS Scientific, New Hope, Pa.). Fivehundred μL of 250 μM purified HbS were diluted into 4.5 mL of HEMOXbuffer (30 mM TES, 130 mM NaCl, 5 mM KCl, pH=7.4) resulting in a finalhemoglobin concentration of 25 μM. The compounds were added at the finaldesired concentrations. The mixture was incubated for 45 min at 37° C.and then transferred to the Hemox sample chamber. The samples weresaturated with oxygen by flushing with compressed air for 10 minutes.The samples were then flushed with pure nitrogen and the absorbance ofdeoxy-Hb was recorded as a function of the solution pO₂. The oxygenequilibrium data was then fit to the Hill Model to obtain values forp50. The deoxygenation curves for both HbS alone (control) and HbS inthe presence of compound were collected with the TCS software. The p50for purified Hbs was typically 13.8±1.6. Delta p50 values were obtainedfrom the p50 value for control minus the p50 value for HbS treated withcompound divided by the p50 value for the control. A positive delta p50value corresponds to a left shifted curve and a lower p50 value relativeto control, indicating that the compound acts to modulate HbS toincrease its affinity for oxygen.

Example 34 Modulation of Hemoglobin Oxygen Affinity by SubstitutedBenzaldehyde Compounds—Assay Results

The compounds of Table 1 that were where tested in the assay above wereall found to have positive delta p50 values. Delta p50% is calculatedfrom [[p50(HbS)−p50(HbS treated with compound)]/p50(HbS)]×100. Table 2below lists the delta p50% values where + indicates a delta p50% ofbetween 0 and 29 and ++ indicates a delta p50% of 30 or greater. Unlessnoted otherwise, the compounds in Table 2 were tested at 30 μM.

TABLE 2 delta p50 Compound delta p50 1 ++ 2 + 3 + (100 μM) 4 + 5 ++ 6 +(100 μM) 7 ++ 8 + 9 + 10 ++ 11 + 12 + (100 μM) 13 + 14 + 15 + (100 μM)16 + 21 + (100 μM) 23 ++ 24 ++ 25 ++ 33 + (100 μM) 34 + 35 + 37 + 38 ++(100 μM)  39 + (100 μM) 40 + 41 42 43 44 45

Example 35 Polymerization Assay

Polymerization assays are carried out in vitro using purified HBSexchanged into 1.8 M potassium phosphate buffer at pH 7.4. Using aslightly modified protocol (Antonini and Brunori, 1971), HbS is purifiedby the CRO VIRUSYS, from blood obtained from homozygous sickle cellpatients through the Hemoglobinopathy Center at Children's HospitalOakland Research Institute (CHORI) with Institutional Review Boardapproval. Compounds are prepared in 100% DMSO and a desired amount isadded to 50 μM of purified HBS at a final DMSO concentration of 0.3%.Final potassium phosphate concentration is adjusted to 1.8 M using acombination of 2.5 M potassium phosphate stock solution and water at pH7.4. The reaction mixture is incubated for an hour at 37° C. and thentransferred into a 24-well plate for deoxygenation in a glove boxcontaining 99.5% nitrogen and 0.5% oxygen. The 24-well plate is notcovered and incubated at 4° C. on a plate cooler inside the glove boxfor one and a half hours. Fifty μL of the reaction mixture istransferred into a 96-well plate and the absorbance at 700 nm ismeasured every minute for one hour at 37° C. in a plate reader locatedinside the glove box. A plot of the absorbance against time is fittedusing a Boltzman sigmoidal fit and the delay time (from zero to time athalf Vmax) is measured. To compare and rank compounds, delay times areexpressed as percent delay (% DT), which is defined as the difference indelay times for HBS/compound and HBS alone multiplied by 100 and dividedby the delay time for HBS alone.

Compounds listed below have been tested in the polymerization assay.Activity ranges are defined by the number of dagger (†) symbolsindicated. † denotes activity ≧40% but ≦80%; †† denotes activity >80%but ≦120%; ††† denotes activity >120% but ≦140%; †††† denotes activity>160%.

Compound % delta Delay 42 †† 43 †† 44 † 45 †† 46 † 47 †† 48 † 49 †

Example 36 R/T Assay

A relaxed-to-tense transition assay (“R/T assay”) was used to determinethe ability of substituted benzaldehyde compounds to maintain thehigh-oxygen affinity relaxed (R) state of hemoglobin under deoxygenatedconditions. This ability can be expressed as a “delta R” value (i.e.,the change in the time-period of the R state after hemoglobin is treatedwith a compound, as compared to the period without treatment with thecompound). Delta R is the % R to remaining after the compounds treatmentcompared with no treatment (e.g. if R % without treatment is 8% whilewith treatment with a target compound is 48% R at 30 μM, then % R is 40%for that compound.

A mixture of HbS/A was purified from blood obtained from homozygoussickle cell patients though the Hemoglobinopathy Center at Children'sHospital Oakland Research Institute (CHORI) with Institutional ReviewBoard approval. HbS/A (at a final concentration of 3 μM) was incubatedfor 1 hr at 37° C. in presence or absence of compounds in 50 μMpotassium phosphate buffer, pH=7.4 and 30 μM 2, 3 diphosphoglycerate(DPG) in 96 well plates in a final volume of 160 μl. Compounds wereadded at different concentrations (3 μM to 100 μM final concentrations).Plates were covered with a Mylar film. After incubation was completedthe Mylar cover was removed and the plates were placed in a SpectrostarNano plate reader previously heated at 37° C. Five minutes later, N₂(flow rate=20 L/min) was flowed through the spectrophotometer.Spectroscopic measurements (300 nm to 700 nm) were taken every 5 min for2 hours. Data analysis was performed by using linear regression from thedata retrieved for all wavelengths.

Table 4 below lists the delta R values where + indicates a delta R ofbetween 0 and 30, ++ indicates a delta R of between 30 and 50, and +++indicates a delta R of 50 or greater. Unless noted otherwise, thecompounds in Table 2 were tested at 9 μM.

TABLE 3 delta R delta R Compound (%) 5 ++ 10 ++ 24 + 25 ++ 41 + 42 +++(30 μm) 43 +++ (30 μm) 44 +++ 45 +++

Example 37 Whole Blood Assay

Oxygen Equilibrium Curves (OEC) of whole blood before and aftertreatment with different concentrations of substituted benzaldehydecompounds were performed as follows using a HEMOX analyzer (TCSScientific, New Hope, Pa.). Blood samples from homozygous sickle cellpatients were obtained though the Hemoglobinopathy Center at Children'sHospital Oakland Research Institute (CHORI) with Institutional ReviewBoard approval. The hematocrit was adjusted to 20% using autologousplasma and the blood samples were incubated for 1 hour at 37° C. inabsence or presence of compounds. 100 μl of these samples were added to5 mL of Hemox buffer (30 mM TES, 130 mM NaCl, 5 mM KCl, pH=7.4) at 37°C. and then transferred to the Hemox sample chamber. The samples weresaturated with oxygen by flushing with compressed air for 10 minutes.The samples were then flushed with pure nitrogen and the respectiveabsorbances of oxy- and deoxy-Hb are recorded as a function of thesolution pO2. The oxygen equilibrium data were then fitted to the HillModel to obtain values for p50. The deoxygenation curves for both wholeblood alone (control) and whole blood in the presence of the compoundwere collected with the TCS software.

Table 5 below lists the delta p50% values where + indicates a delta p50%of between 0 and 29, ++ indicates a delta p50% of between 30 and 50, and+++ indicates a delta p50% of 50 or greater. The compounds in Table 2were tested at 1000 μM. A positive delta p50 value corresponds to a leftshifted curve and a lower p50 value relative to control, indicating thatthe compound acts to modulate HbS to increase its affinity for oxygen.

TABLE 4 delta p50% Values for Whole Blood Assay Compound delta p50% 42 +43 +++ 44 + 45 +

Example 38 Pharmacokinetic Study of Compound 43(HCl Salt) I.V. Study

Sprague Dawley rats were treated with 7.8 mg/Kg of Compound 43 dissolvedin 10% DMA:50% PEG:16% ca vitron. At specified time points 10 μL ofwhole blood/plasma was removed from rats and treated with 490 ul pH 3buffer+500 uL ACN/IS, then shaken for 1 hour, centrifuged for 10 minutesat 57 rpm at 4 C. The supernatant was transferred to a filter plate andcentrifuged at 2000 rpm for 1 minute at 4 C. The samples were thenanalyzed by LC-MS/MS monitoring parent aldehyde. Concentrations in bloodand plasma are shown in Table 5. Key P/K parameters are shown in Table6.

TABLE 5 Compound 43 7.8 mpk IV in rat blood conc (uM) plasma conc (uM)time (min) A B C A B C 0 BLLOQ BLLOQ BLLOQ BLLOQ BLLOQ BLLOQ 5 259 246281 7.56 8.68 7.44 15 287 341 285 8.38 8.42 7.16 30 283 333 292 nosample 8.66 7.1 60 256 203 285 6.12 7.52 7.22 120 263 274 280 3.92 6.025.22 240 248 225 259 3.72 5.24 5.88 480 118 136 22.9 2.06 2.66 3.15 144081.1 85 70.8 1.07 1.38 1.51

TABLE 6 Compound 43 7.8 mpk IV in rat Blood Plasma t½ beta min 749.0619.1 CL ml/min/kg 0.08 4.45 Vss L/kg 0.09 4.11 AUClast min * umol/L215846.3 4114.8

Oral Study

SD Rats were treated by gavage with 44 mg/kg and 100 mg/kg dissolved in10% DMA:90% PEG. At specified time points blood was taken and worked upas described above in the IV Study. Key Parameters are shown in Table 7.

TABLE 7 Compound 43: 2 PO in rats Blood Plasma ratio ratio dose mg/kg 44100 2.27 44 100 2.27 Tmax min 320.00 720.00 200.00 680.00 Cmax umol/L381.33 1096.67 2.88 14.79 44.53 3.01 AUClast min * umol/L 395638.271384101.11 3.50 12517.54 52836.17 4.22

All patents, patent applications, publications and presentationsreferred to herein are incorporated by reference in their entirety. Anyconflict between any reference cited herein and the teaching of thisspecification is to be resolved in favor of the latter. Similarly, anyconflict between an art-recognized definition of a word or phrase and adefinition of the word or phrase as provided in this specification is tobe resolved in favor of the latter.

1.-17. (canceled)
 18. A method for increasing tissue oxygenation in asubject, the method comprising administering to the subject in needthereof a therapeutically effective amount of a compound of Formula (I):

or a tautomer or pharmaceutically acceptable salt thereof, wherein Q isselected from the group consisting of aryl, heteroaryl, andheterocycloalkyl, each optionally substituted with one to three R^(a); Yis O or CR^(1a)R^(1b), where R^(1a) is H or halo and R^(1b) is selectedfrom the group consisting of H, halo, and OH; X is selected from thegroup consisting of O, >CH(CH₂)_(n)R⁸, and C(R⁹)₂ where n is 0 or 1, R⁸is OH, and R⁹ is independently H or halo; or Y—X taken together is—NHC(O)— or —C(O)NH—; R², R³, R⁴, and R⁵ are independently selected fromthe group consisting of hydrogen, halo, R^(b), OR^(d),—O(CH₂)_(z)OR^(d), —O(CH₂)_(z)NR^(d)R^(d), OC(O)R^(e), SR^(d), CN, NO₂,CO₂R^(d), CONR^(d)R^(d), C(O)R^(d), OC(O)NR^(d)R^(d), NR^(d)R^(d),NR^(d)C(O)R^(e), NR^(d)C(O)₂R^(e), NR^(d)C(O)NR^(d)R^(d), S(O)R^(e),S(O)₂R^(e), NR^(d)S(O)₂R^(e), S(O)₂NR^(d)R^(d), and N₃, where z is 0, 1,2, 3, 4, 5, or 6; or R⁵ is —(CH₂)_(p)R^(5a) where p is 0 or 1 and R^(5a)is OH; R⁶ and R⁷ together form oxo or an aldehyde protecting group, orR⁶ together with R^(1b), R⁸, or R⁵ forms a cyclic ether where one ofRib, R⁸, or R^(5a) is O, R⁶ is a bond, and R⁷ is selected from the groupconsisting of OH, C₁₋₈alkoxy, and haloC₁₋₈alkoxy; each R^(a) isindependently selected from the group consisting of halo, oxo, R^(b),OR^(d), O(CH₂)_(u)OR^(d), O(CH₂)_(u)NR^(d)R^(d),O(CH₂)_(u)NR^(d)C(O)R^(e), O(CH₂)_(u)NR^(d)C(O)₂R^(e),O(CH₂)_(u)NR^(d)S(O)₂R^(e), NH₂, —(CH₂)_(k)OC(O)R^(e), —(CH₂)_(k)SR^(d),CN, NO₂, —(CH₂)_(k)CO₂(C₁₋₈alkyl)OH,—(CH₂)_(k)CO₂(C₁₋₈alkyl)(heteroaryl)C(O)(C₁₋₈alkyl), —(CH₂)_(k)CO₂R^(d),—(CH₂)_(k)CONR^(d)R^(d), —(CH₂)_(k)NR^(d)C(O)R^(e),—(CH₂)_(k)NR^(d)C(O)₂R^(e), —(CH₂)_(k)C(O)R^(d),—(CH₂)_(k)OC(O)NR^(d)R^(d), —NR^(d)(CH₂)_(u)OR^(d),—NR^(d)(CH₂)_(u)NR^(d)R^(d), —NR^(d)(CH₂)_(u)NR^(d)C(O)R^(e),—NR^(d)(CH₂)_(u)NR^(d)C(O)₂R^(e), —NR^(d)(CH₂)_(u)NR^(d) S(O)₂R^(e),—(CH₂)_(k)NR^(d)C(O)R^(e), —(CH₂)_(k)NR^(d)C(O)₂R^(d),—(CH₂)_(k)NR^(d)C(O)NR^(d)R^(d), —(CH₂)_(k)S(O)R^(e),—(CH₂)_(k)S(O)₂R^(e), —(CH₂)_(k)NR^(d)S(O)₂R^(e),—(CH₂)_(k)S(O)₂NR^(d)R^(d), N₃, —(CH₂)_(k)aryl optionally substitutedwith one to three R^(c), —NR^(d)(CH₂)_(k)aryl optionally substitutedwith one to three R^(c), —(CH₂)_(k)heteroaryl optionally substitutedwith one to three R^(c), —NR^(d)(CH₂)_(k)heteroaryl optionallysubstituted with one to three R^(c), —(CH₂)_(k)heterocycloalkyloptionally substituted with one to three R^(c), and—NR^(d)(CH₂)_(k)heterocycloalkyl optionally substituted with one tothree R^(c) wherein k is 0, 1, 2, 3, 4, 5, or 6 and u is 1, 2, 3, 4, 5,or 6; each R^(b) is independently selected from the group consisting ofC₁₋₈alkyl, C₂₋₈alkenyl, and C₂₋₈alkynyl, each optionally independentlysubstituted with one to three halo, OR^(d), or NR^(d)R^(d); each R^(c)is independently selected from the group consisting of halo, C₁₋₈alkyl,haloC₁₋₈alkyl, C₂₋₈alkenyl, haloC₂₋₈alkenyl, C₂₋₈alkynyl,haloC₂₋₈alkynyl, (CH₂)_(m)OR^(f), OC(O)R^(g), SR^(f), CN, NO₂, CO₂R^(f),CONR^(f)R^(f), C(O)R^(f), OC(O)NR^(f)R^(f), (CH₂)_(m)NR^(f)R^(f),NR^(f)C(O)R^(g), NR^(f)C(O)₂R^(g), NR_(f)C(O)NR^(f)R^(f), S(O)R^(g),S(O)₂R^(g), NR^(f)S(O)₂R^(g), S(O)₂NR^(f)R^(f), N₃, heteroaryloptionally substituted with one to three R^(h), and heterocycloalkyloptionally substituted with one to three R^(h) wherein m is selectedfrom the group consisting of 0, 1, 2, 3, 4, 5, and 6; each R^(h) isindependently selected from the group consisting of halo, C₁₋₈alkyl,haloC₁₋₈alkyl, OR^(j), OC(O)R, SR^(j), NO₂, CO₂R^(j), CONR^(j)R^(j),C(O)R^(j), OC(O)NR^(j)R^(j), NR^(j)R^(j), NR^(j)C(O)R^(t),NR^(j)C(O)₂R^(t), NR^(j)C(O)NR^(j)R^(j), S(O)₂R^(t), S(O)₂R^(t),NR^(j)S(O)₂R^(t), and S(O)₂NR^(j)R^(j); R^(d), R^(f), and R^(j) are eachindependently selected from the group consisting of hydrogen, C₁₋₈alkyl,haloC₁₋₈alkyl, C₂₋₈alkenyl, haloC₂₋₈alkenyl, C₂₋₈alkynyl, andhaloC₂₋₈alkynyl; and R^(e), R^(g), and R^(t) are each independentlyselected from the group consisting of C₁₋₈ alkyl, haloC₁₋₈alkyl,C₂₋₈alkenyl, haloC₂₋₈alkenyl, C₂₋₈alkynyl, and haloC₂₋₈alkynyl; providedthat X and Y are not both O; provided that when X is O, R^(1b) is notOH; provided that when Y is O, and n is 0, R⁸ is not OH; and providedthat when R⁶ and R⁷ together are oxo, Y is CH₂, X is O or CH₂, and R⁵ isH, halo, OH, CHO, or OCH₃, then Q is V or W; where V is selected fromthe group consisting of:

and naphthalene containing three to four ring nitrogen atoms; wherein Vis optionally substituted with one to three R^(a); provided that when Vis

optionally substituted with one R^(a), then at least one of R², R³, R⁴,and R⁵ is OR^(d); and provided that when V is:

then V is substituted with one to three R^(a); and W is selected fromthe group consisting of pyridin-2-yl, pyridin-3-yl, pyridin-4-yl,

wherein W is optionally substituted with one to three R^(a), and whereinthe wavy line signifies the point of attachment to Y; provided that whenW is pyridin-2-yl, pyridin-3-yl, or pyridine-4-yl, then W is substitutedwith one to three R^(a); and provided that when R⁵ is OH or —NR^(d)R^(d)where each R^(d) is hydrogen or C₁₋₈ alkyl, or —NR^(d)COR^(e) whereR^(d) is hydrogen or C₁₋₈alkyl and R^(c) is C₁₋₈alkyl, and R², R³ and R⁴are independently hydrogen, halo, C₁₋₈alkyl optionally substituted withone to three halo, OC₁₋₈ alkyl, or OH, then Q is not aryl substitutedwith R^(a) where R^(a) is cyano, carboxy or tetrazolyl.
 19. A method fortreating a condition associated with oxygen deficiency in a subject, themethod comprising administering to the subject in need thereof atherapeutically effective amount of a compound of Formula (I):

or a tautomer or pharmaceutically acceptable salt thereof, wherein Q isselected from the group consisting of aryl, heteroaryl, andheterocycloalkyl, each optionally substituted with one to three R^(a); Yis O or CR^(1a)R^(1b), where R^(1a) is H or halo and R^(1b) is selectedfrom the group consisting of H, halo, and OH; X is selected from thegroup consisting of O, >CH(CH₂)_(n)R⁸, and C(R⁹)₂ where n is 0 or 1, R⁸is OH, and R⁹ is independently H or halo; or Y—X taken together is—NHC(O)— or —C(O)NH—; R², R³, R⁴, and R⁵ are independently selected fromthe group consisting of hydrogen, halo, R^(b), OR^(d),—O(CH₂)_(z)OR^(d), —O(CH₂)_(z)NR^(d)R^(d), OC(O)R^(e), SR^(d), CN, NO₂,CO₂R^(d), CONR^(d)R^(d), C(O)R^(d), OC(O)NR^(d)R^(d), NR^(d)R^(d),NR^(d)C(O)R^(e), NR^(d)C(O)₂R^(e), NR^(d)C(O)NR^(d)R^(d), S(O)R^(e),S(O)₂R^(e), NR^(d)S(O)₂R^(e), S(O)₂NR^(d)R^(d), and N₃, where z is 0, 1,2, 3, 4, 5, or 6; or R⁵ is —(CH₂)_(p)R^(5a) where p is 0 or 1 and R^(5a)is OH; R⁶ and R⁷ together form oxo or an aldehyde protecting group, orR⁶ together with R^(1b), R⁸, or R⁵ forms a cyclic ether where one ofRib, R⁸, or R^(5a) is O, R⁶ is a bond, and R⁷ is selected from the groupconsisting of OH, C₁₋₈alkoxy, and haloC₁₋₈alkoxy; each R^(a) isindependently selected from the group consisting of halo, oxo, R^(b),OR^(d), O(CH₂)_(u)OR^(d), O(CH₂)_(u)NR^(d)R^(d),O(CH₂)_(u)NR^(d)C(O)R^(e), O(CH₂)_(u)NR^(d)C(O)₂R^(e),O(CH₂)_(u)NR^(d)S(O)₂R^(e), NH₂, —(CH₂)_(k)OC(O)R^(e), —(CH₂)_(k)SR^(d),CN, NO₂, —(CH₂)_(k)CO₂(C₁₋₈alkyl)OH,—(CH₂)_(k)CO₂(C₁₋₈alkyl)(heteroaryl)C(O)(C₁₋₈alkyl), —(CH₂)_(k)CO₂R^(d),—(CH₂)_(k)CONR^(d)R^(d), —(CH2)_(k)NR^(d)C(O)R^(e),—(CH₂)_(k)NR^(d)C(O)₂R^(e), —(CH₂)_(k)C(O)R^(d),—(CH₂)_(k)OC(O)NR^(d)R^(d), —NR^(d)(CH₂)_(u)OR^(d),—NR^(d)(CH₂)_(u)NR^(d)R^(d), —NR^(d)(CH₂)_(u)NR^(d)C(O)R^(e),—NR^(d)(CH₂)_(u)NR^(d)C(O)₂R^(e), —NR^(d)(CH₂)_(u)NR^(d) S(O)₂R^(e),—(CH₂)_(k)NR^(d)C(O)R^(e), —(CH₂)_(k)NR^(d)C(O)₂R^(d),—(CH₂)_(k)NR^(d)C(O)NR^(d)R^(d), —(CH₂)_(k)S(O)R^(e),—(CH₂)_(k)S(O)₂R^(e), —(CH₂)_(k)NR^(d)S(O)₂R^(e),—(CH₂)_(k)S(O)₂NR^(d)R^(d), N₃, —(CH₂)_(k)aryl optionally substitutedwith one to three R^(c), —NR^(d)(CH₂)_(k)aryl optionally substitutedwith one to three R^(c), —(CH₂)_(k)heteroaryl optionally substitutedwith one to three R^(c), —NR^(d)(CH₂)_(k)heteroaryl optionallysubstituted with one to three R^(c), —(CH₂)_(k)heterocycloalkyloptionally substituted with one to three R^(c), and—NR^(d)(CH₂)_(k)heterocycloalkyl optionally substituted with one tothree R^(c) wherein k is 0, 1, 2, 3, 4, 5, or 6 and u is 1, 2, 3, 4, 5,or 6; each R^(b) is independently selected from the group consisting ofC₁₋₈alkyl, C₂₋₈alkenyl, and C₂₋₈alkynyl, each optionally independentlysubstituted with one to three halo, OR^(d), or NR^(d)R^(d); each R^(c)is independently selected from the group consisting of halo, C₁₋₈alkyl,haloC₁₋₈alkyl, C₂₋₈alkenyl, haloC₂₋₈alkenyl, C₂₋₈alkynyl,haloC₂₋₈alkynyl, (CH₂)_(m)OR^(f), OC(O)R^(g), SR^(f), CN, NO₂, CO₂R^(f),CONR^(f)R^(f), C(O)R^(f), OC(O)NR^(f)R^(f), (CH₂)_(m)NR^(f)R^(f),NR^(f)C(O)R^(g), NR^(f)C(O)₂R^(g), NR_(f)C(O)NR^(f)R^(f), S(O)R^(g),S(O)₂R^(g), NR^(f)S(O)₂R^(g), S(O)₂NR^(f)R^(f), N₃, heteroaryloptionally substituted with one to three R^(h), and heterocycloalkyloptionally substituted with one to three R^(h) where m is selected fromthe group consisting of 0, 1, 2, 3, 4, 5, and 6; each R^(h) isindependently selected from the group consisting of halo, C₁₋₈alkyl,haloC₁₋₈alkyl, OR^(j), OC(O)R, SR^(j), NO₂, CO₂R^(j), CONR^(j)R^(j),C(O)R^(j), OC(O)NR^(j)R^(j), NR^(j)R^(j), NR^(j)C(O)R^(t),NR^(j)C(O)₂R^(t), NR^(j)C(O)NR^(j)R^(j), S(O)R^(t), S(O)₂R^(t),NR^(j)S(O)₂R^(t), and S(O)₂NR^(j)R^(j); R^(d), R^(f), and R^(j) are eachindependently selected from the group consisting of hydrogen, C₁₋₈alkyl,haloC₁₋₈alkyl, C₂₋₈alkenyl, haloC₂₋₈alkenyl, C₂₋₈alkynyl, andhaloC₂₋₈alkynyl; and R^(e), R^(g), and R^(t) are each independentlyselected from the group consisting of C₁₋₈ alkyl, haloC₁₋₈alkyl,C₂₋₈alkenyl, haloC₂₋₈alkenyl, C₂₋₈alkynyl, and haloC₂₋₈alkynyl; providedthat X and Y are not both O; provided that when X is O, R^(1b) is notOH; provided that when Y is O, and n is 0, R⁸ is not OH; and providedthat when R⁶ and R⁷ together are oxo, Y is CH₂, X is O or CH₂, and R⁵ isH, halo, OH, CHO, or OCH₃, then Q is V or W; where V is selected fromthe group consisting of:

and naphthalene containing three to four ring nitrogen atoms; wherein Vis optionally substituted with one to three R^(a); provided that when Vis

optionally substituted with one R^(a), then at least one of R², R³, R⁴,and R⁵ is OR^(d); and provided that when V is:

then V is substituted with one to three R^(a); and W is selected fromthe group consisting of pyridin-2-yl, pyridin-3-yl, pyridin-4-yl,

wherein W is optionally substituted with one to three R^(a), and whereinthe wavy line signifies the point of attachment to Y; provided that whenW is pyridin-2-yl, pyridin-3-yl, or pyridine-4-yl, then W is substitutedwith one to three R^(a); and provided that when R⁵ is OH or —NR^(d)R^(d)where each R^(d) is hydrogen or C₁₋₈alkyl, or —NR^(d)COR^(e) where R^(d)is hydrogen or C₁₋₈alkyl and R^(c) is C₁₋₈alkyl, and R², R³ and R⁴ areindependently hydrogen, halo, C₁₋₈alkyl optionally substituted with oneto three halo, OC₁₋₈alkyl, or OH, then Q is not aryl substituted withR^(a) where R^(a) is cyano, carboxy or tetrazolyl.
 20. The method ofclaim 19, wherein the condition is selected from the group consisting ofsickle cell disease, cancer, a pulmonary disorder, stroke, high altitudesickness, an ulcer, a pressure sore, Alzheimer's disease, acuterespiratory distress syndrome, and a wound.
 21. The method of claim 20,wherein the condition is sickle cell disease.
 22. The method of claim20, wherein the condition is acute respiratory distress syndrome. 23.The method of claim 20, wherein the condition is a pulmonary disorder.24. The method of claim 18, wherein Q is selected from the groupconsisting of heteroaryl and heterocycloalkyl, each of which isoptionally substituted with one to three R^(a).
 25. The method of claim18, wherein: Y is O or CH₂; X is O or CH₂; Q is selected from the groupconsisting of: i) imidazopyridinyl, methylimidazopyridinyl, indazolyl,pyrrolopyridinyl, pyrrolopyrazinyl, pyrazolopyridinyl,pyrazolopyrazinyl, and quinolinyl, each of which is optionallysubstituted with one to three R^(a); wherein R², R³, R⁴, and R⁵, areindependently selected from the group consisting of hydrogen, halo,R^(b), OR^(d), O(CH₂)_(z)OR^(d), O(CH₂)_(z)NR^(d)R^(d), OC(O)R^(e),SR^(d), CN, NO₂, CO₂R^(d), CONR^(d)R^(d), C(O)R^(d), OC(O)NR^(d)R^(d),NR^(d)R^(d), NR^(d)C(O)R^(e), NR^(d)C(O)₂R^(e), NR^(d)C(O)NR^(d)R^(d),S(O)R^(e), S(O)₂R^(e), NR^(d)S(O)₂R^(e), S(O)₂NR^(d)R^(d), and N₃ wherez is 1, 2, or 3; and ii) pyridinyl and piperidinyl, each of which isoptionally substituted with one to three R^(a); wherein R², R³, and R⁴are independently selected from the group consisting of hydrogen, halo,R^(b), OR^(d), O(CH₂)_(z)OR^(d), O(CH₂)_(z)NR^(d)R^(d), OC(O)R^(e),SR^(d), CN, NO₂, CO₂R^(d), CONR^(d)R^(d), C(O)R^(d), OC(O)NR^(d)R^(d),NR^(d)R^(d), NR^(d)C(O)R^(e), NR^(d)C(O)₂R^(e), NR^(d)C(O)NR^(d)R^(d),S(O)R^(e), S(O)₂R^(e), NR^(d)S(O)₂R^(e), S(O)₂NR^(d)R^(d), and N₃ wherez is 1, 2, or 3; and R⁵ is selected from the group consisting of haloand OR^(d); R⁶ and R⁷ together form oxo or an aldehyde protecting group;each R^(a) is independently selected from the group consisting of halo,oxo, R^(b), OR^(d), O(CH₂)_(u)OR^(d), O(CH₂)_(u)NR^(d)R^(d),O(CH₂)_(u)NR^(d)C(O)R^(e), O(CH₂)_(u)NR^(d)C(O)₂R^(e),O(CH₂)_(u)NR^(d)S(O)₂R^(e), NH₂, —(CH₂)_(k)OC(O)R^(e), —(CH₂)_(k)SR^(d),CN, NO₂, —(CH₂)_(k)CO₂(C₁₋₈alkyl)OH, —(CH₂)_(k)CO₂(C₁₋₈alkyl)(heteroaryl)C(O)(C₁₋₈alkyl), —(CH₂)_(k)CO₂R^(d),—(CH₂)_(k)CONR^(d)R^(d), —(CH₂)_(k)NR^(d)C(O)R^(e),—(CH₂)_(k)NR^(d)C(O)₂R^(e), —(CH₂)_(k)C(O)R^(d),—(CH₂)_(k)OC(O)NR^(d)R^(d), —NR^(d)(CH₂)_(u)OR^(d),—NR^(d)(CH₂)_(u)NR^(d)R^(d), —NR^(d)(CH₂)_(u)NR^(d)C(O)R^(e),—NR^(d)(CH₂)_(u)NR^(d)C(O)₂R^(e), —NR^(d)(CH₂)_(u)NR^(d)S(O)₂R^(e),—(CH₂)_(k)NR^(d)C(O)R^(e), —(CH₂)_(k)NR^(d)C(O)₂R^(d),—(CH₂)_(k)NR^(d)C(O)NR^(d)R^(d), —(CH₂)_(k)S(O)R^(e),—(CH₂)_(k)S(O)₂R^(e), —(CH₂)_(k)NR^(d)S(O)₂R^(e),—C(O)(CH₂)_(k)NR^(d)S(O)₂R^(e), —(CH₂)_(k)C(O)NR^(d)S(O)₂R^(e),—(CH₂)_(k)S(O)₂NR^(d)R^(d), N₃, —(CH₂)_(k)aryl optionally substitutedwith one to three R^(c), —NR^(d)(CH₂)_(k)aryl optionally substitutedwith one to three R^(c), —(CH₂)_(k)heteroaryl optionally substitutedwith one to three R^(c), —NR^(d)(CH₂)_(k)heteroaryl optionallysubstituted with one to three R^(c), —(CH₂)_(k)heterocycloalkyloptionally substituted with one to three R^(c), and—NR^(d)(CH₂)_(k)heterocycloalkyl optionally substituted with one tothree R^(c) where k is 0, 1, 2, 3, 4, 5, or 6 and u is 1, 2, 3, 4, 5, or6; each R^(b) is independently selected from the group consisting ofC₁₋₈alkyl, C₂₋₈alkenyl, and C₂₋₈alkynyl, each optionally independentlysubstituted with one to three halo, OR^(d), or NR^(d)R^(d); each R^(c)is independently selected from the group consisting of halo, C₁₋₈ alkyl,haloC₁₋₈alkyl, C₂₋₈alkenyl, haloC₂₋₈alkenyl, C₂₋₈alkynyl,haloC₂₋₈alkynyl, (CH₂)_(m)OR^(f), OC(O)R^(g), SR^(f), CN, NO₂,(CH₂)_(m)CO₂R^(f), CONR^(f)R^(f), C(O)R^(f), OC(O)NR^(f)R^(f),(CH₂)_(m)NR^(f)R^(f), NR^(f)C(O)R^(g), NR^(f)C(O)₂R^(g),NR^(f)C(O)NR^(f)R^(f), S(O)R^(g), S(O)₂R^(g), NR^(f)S(O)₂R^(g),S(O)₂NR^(f)R^(f), N₃, (R^(f))_(m)SiC₁₋₈ alkyl, heteroaryl optionallysubstituted with one to three R^(h), cycloalkyl optionally substitutedwith one to three R^(h), and heterocycloalkyl optionally substitutedwith one to three R^(h) wherein m is selected from the group consistingof 0, 1, 2, 3, 4, 5, and 6; each R^(h) is independently selected fromthe group consisting of halo, C₁₋₈ alkyl, haloC₁₋₈alkyl, OR^(j), OC(O)R,SR^(j), NO₂, CO₂R^(j), CONR^(j)R^(j), C(O)R^(j), OC(O)NR^(j)R^(j),NR^(j)R^(j), NR^(j)C(O)R^(t), NR^(j)C(O)₂R^(t), NR^(j)C(O)NR^(j)R^(j),S(O)R^(t), S(O)₂R^(t), NR^(j)S(O)₂R^(t), and S(O)₂NR^(j)R^(j); R^(d),R^(f), and R^(j) are each independently selected from the groupconsisting of hydrogen, C₁₋₈ alkyl, haloC₁₋₈alkyl, C₂₋₈ alkenyl,haloC₂₋₈alkenyl, C₂₋₈ alkynyl, and haloC₂₋₈alkynyl; and R^(e), R^(g),and R^(t) are each independently selected from the group consisting ofC₁₋₈alkyl, haloC₁₋₈alkyl, C₂₋₈ alkenyl, haloC₂₋₈alkenyl, C₂₋₈ alkynyl,and haloC₂₋₈alkynyl; and R⁶ and R⁷ together form oxo.
 26. The method ofclaim 18, wherein: Y is CH₂; and X is CH₂; and R⁶ and R⁷ together formoxo.
 27. The method of claim 25, wherein Q is selected from the groupconsisting of imidazo[1,5-a]pyridin-8-yl, imidazo[1,5-a]pyridin-6-yl,imidazo[1,5-a]pyridin-5-yl, imidazo[1,2-a]pyridin-8-yl,imidazo[1,2-a]pyridin-7-yl, imidazo[1,2-a]pyridin-6-yl,imidazo[1,2-a]pyridin-5-yl, imidazo[1,2-a]pyridin-3-yl,8-methylimidazo[1,2-a]pyridin-2-yl, indazol-4-yl,pyrrolo[2,3-b]pyridin-4-yl, pyrrolo[1,2-a]pyrazin-6-yl,pyrrolo[1,2-a]pyrazin-4-yl, pyrazolo[3,4-b]pyridin-4-yl,pyrazolo[1,5-a]pyrazin-3-yl, and quinolin-5-yl, each of which isoptionally substituted with one to three R^(a).
 28. The method of claim27, wherein: R² is selected from the group consisting of H and OR^(d);R³ is selected from the group consisting of H, CN, halo, and OR^(d); R⁴is selected from the group consisting of H, CN, and OR^(d); and R⁵ is H.29. The method of claim 18, wherein Q is selected from the groupconsisting of pyridin-3-yl and piperidin-1-yl, each of which isoptionally substituted with one to three R^(a).
 30. The method of claim29, wherein R⁵ is selected from the group consisting of hydroxy andfluoro.
 31. The method of claim 18, wherein the compound or a tautomeror pharmaceutically acceptable salt thereof, is selected from the groupconsisting of:2-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-5-methoxy-benzaldehyde,2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-benzaldehyde,2-hydroxy-6-((2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)pyridin-3-yl)-methoxy)benzaldehyde,2-hydroxy-6-((2-(1-(3,3,3-trifluoropropyl)-1H-pyrazol-5-yl)pyridin-3-yl)-methoxy)benzaldehyde,2-fluoro-6-((2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)pyridin-3-yl)-methoxy)benzaldehyde,2-fluoro-6-((2-(1-(3,3,3-trifluoropropyl)-1H-pyrazol-5-yl)pyridin-3-yl)-methoxy)benzaldehyde,and2-fluoro-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-benzaldehyde,or a tautomer or pharmaceutically acceptable salt thereof.
 32. Themethod of claim 18, wherein the compound is2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-benzaldehyde;or a tautomer or a pharmaceutically acceptable salt thereof.
 33. Themethod of claim 32 wherein the compound is2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde.34. The method of claim 21, wherein Q is selected from the groupconsisting of heteroaryl and heterocycloalkyl, each of which isoptionally substituted with one to three R^(a).
 35. The method of claim21, wherein: Y is O or CH₂; X is O or CH₂; Q is selected from the groupconsisting of: i) imidazopyridinyl, methylimidazopyridinyl, indazolyl,pyrrolopyridinyl, pyrrolopyrazinyl, pyrazolopyridinyl,pyrazolopyrazinyl, and quinolinyl, each of which is optionallysubstituted with one to three R^(a); wherein R², R³, R⁴, and R⁵, areindependently selected from the group consisting of hydrogen, halo,R^(b), OR^(d), O(CH₂)_(z)OR^(d), O(CH₂)_(z)NR^(d)R^(d), OC(O)R^(e),SR^(d), CN, NO₂, CO₂R^(d), CONR^(d)R^(d), C(O)R^(d), OC(O)NR^(d)R^(d),NR^(d)R^(d), NR^(d)C(O)R^(e), NR^(d)C(O)₂R^(e), NR^(d)C(O)NR^(d)R^(d),S(O)R^(e), S(O)₂R^(e), NR^(d)S(O)₂R^(e), S(O)₂NR^(d)R^(d), and N₃ wherez is 1, 2, or 3; and (ii) pyridinyl and piperidinyl, each of which isoptionally substituted with one to three R^(a); wherein R², R³, and R⁴are independently selected from the group consisting of hydrogen, halo,R^(b), OR^(d), O(CH₂)_(z)OR^(d), O(CH₂)_(z)NR^(d)R^(d), OC(O)R^(e),SR^(d), CN, NO₂, CO₂R^(d), CONR^(d)R^(d), C(O)R^(d), OC(O)NR^(d)R^(d),NR^(d)R^(d), NR^(d)C(O)R^(e), NR^(d)C(O)₂R^(e), NR^(d)C(O)NR^(d)R^(d),S(O)R^(e), S(O)₂R^(e), NR^(d)S(O)₂R^(e), S(O)₂NR^(d)R^(d), and N₃ wherez is 1, 2, or 3; and R⁵ is selected from the group consisting of haloand OR^(d); R⁶ and R⁷ together form oxo or an aldehyde protecting group;each R^(a) is independently selected from the group consisting of halo,oxo, R^(b), OR^(d), O(CH₂)_(u)OR^(d), O(CH₂)_(u)NR^(d)R^(d),O(CH₂)_(u)NR^(d)C(O)R^(e), O(CH₂)_(u)NR^(d)C(O)₂R^(e),O(CH₂)_(u)NR^(d)S(O)₂R^(e), NH₂, —(CH₂)_(k)OC(O)R^(e), —(CH₂)_(k)SR^(d),CN, NO₂, —(CH₂)_(k)CO₂(C₁₋₈alkyl)OH,—(CH₂)_(k)CO₂(C₁₋₈alkyl)(heteroaryl)C(O)(C₁₋₈alkyl), —(CH₂)_(k)CO₂R^(d),—(CH₂)_(k)CONR^(d)R^(d), —(CH₂)_(k)NR^(d)C(O)R^(e),—(CH₂)_(k)NR^(d)C(O)₂R^(e), —(CH₂)_(k)C(O)R^(d),—(CH₂)_(k)OC(O)NR^(d)R^(d), —NR^(d)(CH₂)_(u)OR^(d),—NR^(d)(CH₂)_(u)NR^(d)R^(d), —NR^(d)(CH₂)_(u)NR^(d)C(O)R^(e),—NR^(d)(CH₂)_(u)NR^(d)C(O)₂R^(e), —NR^(d)(CH₂)_(u)NR^(d)S(O)₂R^(e),—(CH₂)_(k)NR^(d)C(O)R^(e), —(CH₂)_(k)NR^(d)C(O)₂R^(d),—(CH₂)_(k)NR^(d)C(O)NR^(d)R^(d), —(CH₂)_(k)S(O)R^(e),—(CH₂)_(k)S(O)₂R^(e), —(CH₂)_(k)NR^(d)S(O)₂R^(e),—C(O)(CH₂)_(k)NR^(d)S(O)₂R^(e), —(CH₂)_(k)C(O)NR^(d)S(O)₂R^(e),—(CH₂)_(k)S(O)₂NR^(d)R^(d), N₃, —(CH₂)_(k)aryl optionally substitutedwith one to three R^(c), —NR^(d)(CH₂)_(k)aryl optionally substitutedwith one to three R^(c), —(CH₂)_(k)heteroaryl optionally substitutedwith one to three R^(c), —NR^(d)(CH₂)_(k)heteroaryl optionallysubstituted with one to three R^(c), —(CH₂)_(k)heterocycloalkyloptionally substituted with one to three R^(c), and—NR^(d)(CH₂)_(k)heterocycloalkyl optionally substituted with one tothree R^(c) where k is 0, 1, 2, 3, 4, 5, or 6 and u is 1, 2, 3, 4, 5, or6; each R^(b) is independently selected from the group consisting ofC₁₋₈alkyl, C₂₋₈alkenyl, and C₂₋₈alkynyl, each optionally independentlysubstituted with one to three halo, OR^(d), or NR^(d)R^(d); each R^(c)is independently selected from the group consisting of halo, C₁₋₈ alkyl,haloC₁₋₈alkyl, C₂₋₈alkenyl, haloC₂₋₈alkenyl, C₂₋₈alkynyl,haloC₂₋₈alkynyl, (CH₂)_(m)OR^(f), OC(O)R^(g), SR^(f), CN, NO₂,(CH₂)_(m)CO₂R^(f), CONR^(f)R^(f), C(O)R^(f), OC(O)NR^(f)R^(f),(CH₂)_(m)NR^(f)R^(f), NR^(f)C(O)R^(g), NR^(f)C(O)₂R^(g),NR^(f)C(O)NR^(f)R^(f), S(O)R^(g), S(O)₂R^(g), NR^(f)S(O)₂R^(g),S(O)₂NR^(f)R^(f), N₃, (R^(f))_(m)SiC₁₋₈alkyl, heteroaryl optionallysubstituted with one to three R^(h), cycloalkyl optionally substitutedwith one to three R^(h), and heterocycloalkyl optionally substitutedwith one to three R^(h) where m is selected from the group consisting of0, 1, 2, 3, 4, 5, and 6; each R^(h) is independently selected from thegroup consisting of halo, C₁₋₈ alkyl, haloC₁₋₈alkyl, OR^(j), OC(O)R,SR^(j), NO₂, CO₂R^(j), CONR^(j)R^(j), C(O)R^(j), OC(O)NR^(j)R^(j),NR^(j)R^(j), NR^(j)C(O)R^(t), NR^(j)C(O)₂R^(t), NR^(j)C(O)NR^(j)R^(j),S(O)R^(t), S(O)₂R^(t), NR^(j)S(O)₂R^(t), and S(O)₂NR^(j)R^(j); R^(d),R^(f), and R^(j) are each independently selected from the groupconsisting of hydrogen, C₁₋₈ alkyl, haloC₁₋₈alkyl, C₂₋₈ alkenyl,haloC₂₋₈alkenyl, C₂₋₈ alkynyl, and haloC₂₋₈alkynyl; and R^(e), R^(g),and R^(t) are each independently selected from the group consisting ofC₁₋₈alkyl, haloC₁₋₈alkyl, C₂₋₈ alkenyl, haloC₂₋₈alkenyl, C₂₋₈ alkynyl,and haloC₂₋₈alkynyl; and R⁶ and R⁷ together form oxo.
 36. The method ofclaim 21, wherein: Y is CH₂; and X is CH₂; and R⁶ and R⁷ together formoxo.
 37. The method of claim 35, wherein Q is selected from the groupconsisting of imidazo[1,5-a]pyridin-8-yl, imidazo[1,5-a]pyridin-6-yl,imidazo[1,5-a]pyridin-5-yl, imidazo[1,2-a]pyridin-8-yl,imidazo[1,2-a]pyridin-7-yl, imidazo[1,2-a]pyridin-6-yl,imidazo[1,2-a]pyridin-5-yl, imidazo[1,2-a]pyridin-3-yl,8-methylimidazo[1,2-a]pyridin-2-yl, indazol-4-yl,pyrrolo[2,3-b]pyridin-4-yl, pyrrolo[1,2-a]pyrazin-6-yl,pyrrolo[1,2-a]pyrazin-4-yl, pyrazolo[3,4-b]pyridin-4-yl,pyrazolo[1,5-a]pyrazin-3-yl, and quinolin-5-yl, each of which isoptionally substituted with one to three R^(a).
 38. The method of claim37, wherein: R² is selected from the group consisting of H and OR^(d);R³ is selected from the group consisting of H, CN, halo, and OR^(d); R⁴is selected from the group consisting of H, CN, and OR^(d): and R⁵ is H.39. The method of claim 21, wherein Q is selected from the groupconsisting of pyridin-3-yl and piperidin-1-yl, each of which isoptionally substituted with one to three R^(a).
 40. The method of claim39, wherein R⁵ is selected from the group consisting of hydroxy andfluoro.
 41. The method of claim 21, wherein the compound or a tautomeror pharmaceutically acceptable salt thereof, is selected from the groupconsisting of:2-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-5-methoxy-benzaldehyde,2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-benzaldehyde,2-hydroxy-6-((2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)pyridin-3-yl)-methoxy)benzaldehyde,2-hydroxy-6-((2-(1-(3,3,3-trifluoropropyl)-1H-pyrazol-5-yl)pyridin-3-yl)-methoxy)benzaldehyde,2-fluoro-6-((2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)pyridin-3-yl)-methoxy)benzaldehyde,2-fluoro-6-((2-(1-(3,3,3-trifluoropropyl)-1H-pyrazol-5-yl)pyridin-3-yl)-methoxy)benzaldehyde,and2-fluoro-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-benzaldehyde,or a tautomer or pharmaceutically acceptable salt thereof.
 42. Themethod of claim 21, wherein the compound is2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-benzaldehyde,or a tautomer or a pharmaceutically acceptable salt thereof.
 43. Themethod of claim 42, wherein the compound is2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde.44. The method of claim 23, wherein Q is selected from the groupconsisting of heteroaryl and heterocycloalkyl, each optionallysubstituted with one to three R^(a).
 45. The method of claim 23,wherein: Y is O or CH₂; X is O or CH₂; Q is selected from the groupconsisting of: i) imidazopyridinyl, methylimidazopyridinyl, indazolyl,pyrrolopyridinyl, pyrrolopyrazinyl, pyrazolopyridinyl,pyrazolopyrazinyl, and quinolinyl, each of which is optionallysubstituted with one to three R^(a); wherein R², R³, R⁴, and R⁵, areindependently selected from the group consisting of hydrogen, halo,R^(b), OR^(d), O(CH₂)_(z)OR^(d), O(CH₂)_(z)NR^(d)R^(d), OC(O)R^(e),SR^(d), CN, NO₂, CO₂R^(d), CONR^(d)R^(d), C(O)R^(d), OC(O)NR^(d)R^(d),NR^(d)R^(d), NR^(d)C(O)R^(e), NR^(d)C(O)₂R^(e), NR^(d)C(O)NR^(d)R^(d),S(O)R^(e), S(O)₂R^(e), NR^(d)S(O)₂R^(e), S(O)₂NR^(d)R^(d), and N₃ wherez is 1, 2, or 3; and ii) pyridinyl and piperidinyl, each of which isoptionally substituted with one to three R^(a); wherein R², R³, and R⁴are independently selected from the group consisting of hydrogen, halo,R^(b), OR^(d), O(CH₂)_(z)OR^(d), O(CH₂)_(z)NR^(d)R^(d), OC(O)R^(e),SR^(d), CN, NO₂, CO₂R^(d), CONR^(d)R^(d), C(O)R^(d), OC(O)NR^(d)R^(d),NR^(d)R^(d), NR^(d)C(O)R^(e), NR^(d)C(O)₂R^(e), NR^(d)C(O)NR^(d)R^(d),S(O)R^(e), S(O)₂R^(e), NR^(d)S(O)₂R^(e), S(O)₂NR^(d)R^(d), and N₃ wherez is 1, 2, or 3; and R⁵ is selected from the group consisting of haloand OR^(d); R⁶ and R⁷ together form oxo or an aldehyde protecting group;each R^(a) is independently selected from the group consisting of halo,oxo, R^(b), OR^(d), O(CH₂)_(u)OR^(d), O(CH₂)_(u)NR^(d)R^(d),O(CH₂)_(u)NR^(d)C(O)R^(e), O(CH₂)_(u)NR^(d)C(O)₂R^(e),O(CH₂)_(u)NR^(d)S(O)₂R^(e), NH₂, —(CH₂)_(k)OC(O)R^(e), —(CH₂)_(k)SR^(d),CN, NO₂, —(CH₂)_(k)CO₂(C₁₋₈alkyl)OH,—(CH₂)_(k)CO₂(C₁₋₈alkyl)(heteroaryl)C(O)(C₁₋₈alkyl), —(CH₂)_(k)CO₂R^(d),—(CH₂)_(k)CONR^(d)R^(d), —(CH₂)_(k)NR^(d)C(O)R^(e),—(CH₂)_(k)NR^(d)C(O)₂R^(e), —(CH₂)_(k)C(O)R^(d),—(CH₂)_(k)OC(O)NR^(d)R^(d), —NR^(d)(CH₂)_(u)OR^(d),—NR^(d)(CH₂)_(u)NR^(d)R^(d), —NR^(d)(CH₂)_(u)NR^(d)C(O)R^(e),—NR^(d)(CH₂)_(u)NR^(d)C(O)₂R^(e), —NR^(d)(CH₂)_(u)NR^(d)S(O)₂R^(e),—(CH₂)_(k)NR^(d)C(O)R^(e), —(CH₂)_(k)NR^(d)C(O)₂R^(d),—(CH₂)_(k)NR^(d)C(O)NR^(d)R^(d), —(CH₂)_(k)S(O)R^(e),—(CH₂)_(k)S(O)₂R^(e), —(CH₂)_(k)NR^(d)S(O)₂R^(e),—C(O)(CH₂)_(k)NR^(d)S(O)₂R^(e), —(CH₂)_(k)C(O)NR^(d)S(O)₂R^(e),—(CH₂)_(k)S(O)₂NR^(d)R^(d), N₃, —(CH₂)_(k)aryl optionally substitutedwith one to three R^(c), —NR^(d)(CH₂)_(k)aryl optionally substitutedwith one to three R^(c), —(CH₂)_(k)heteroaryl optionally substitutedwith one to three R^(c), —NR^(d)(CH₂)_(k)heteroaryl optionallysubstituted with one to three R^(c), —(CH₂)_(k)heterocycloalkyloptionally substituted with one to three R^(c), and—NR^(d)(CH₂)_(k)heterocycloalkyl optionally substituted with one tothree R^(c) where k is 0, 1, 2, 3, 4, 5, or 6 and u is 1, 2, 3, 4, 5, or6; each R^(b) is independently selected from the group consisting ofC₁₋₈alkyl, C₂₋₈alkenyl, and C₂₋₈alkynyl, each optionally independentlysubstituted with one to three halo, OR^(d), or NR^(d)R^(d); each R^(c)is independently selected from the group consisting of halo, C₁₋₈ alkyl,haloC₁₋₈alkyl, C₂₋₈alkenyl, haloC₂₋₈alkenyl, C₂₋₈alkynyl,haloC₂₋₈alkynyl, (CH₂)_(m)OR^(f), OC(O)R^(g), SR^(f), CN, NO₂,(CH₂)_(m)CO₂R^(f), CONR^(f)R^(f), C(O)R^(f), OC(O)NR^(f)R^(f),(CH₂)_(m)NR^(f)R^(f), NR^(f)C(O)R^(g), NR^(f)C(O)₂R^(g),NR^(f)C(O)NR^(f)R^(f), S(O)R^(g), S(O)₂R^(g), NR^(f)S(O)₂R^(g),S(O)₂NR^(f)R^(f), N₃, (R^(f))_(m)SiC₁₋₈ alkyl, heteroaryl optionallysubstituted with one to three R^(h), cycloalkyl optionally substitutedwith one to three R^(h), and heterocycloalkyl optionally substitutedwith one to three R^(h) where m is selected from the group consisting of0, 1, 2, 3, 4, 5, and 6; each R^(h) is independently selected from thegroup consisting of halo, C₁₋₈alkyl, haloC₁₋₈alkyl, OR^(j), OC(O)R,SR^(j), NO₂, CO₂R^(j), CONR^(j)R^(j), C(O)R^(j), OC(O)NR^(j)R^(j),NR^(j)R^(j), NR^(j)C(O)R^(t), NR^(j)C(O)₂R^(t), NR^(j)C(O)NR^(j)R^(j),S(O)R^(t), S(O)₂R^(t), NR^(j)S(O)₂R^(t), and S(O)₂NR^(j)R^(j); R^(d),R^(f), and R^(j) are each independently selected from the groupconsisting of hydrogen, C₁₋₈ alkyl, haloC₁₋₈alkyl, C₂₋₈ alkenyl,haloC₂₋₈alkenyl, C₂₋₈alkynyl, and haloC₂₋₈alkynyl; and R^(e), R^(g), andR^(t) are each independently selected from the group consisting ofC₁₋₈alkyl, haloC₁₋₈alkyl, C₂₋₈ alkenyl, haloC₂₋₈alkenyl, C₂₋₈ alkynyl,and haloC₂₋₈alkynyl; and R⁶ and R⁷ together form oxo.
 46. The method ofclaim 23, wherein: Y is CH₂; and X is CH₂; and R⁶ and R⁷ together formoxo.
 47. The method of claim 45, wherein Q is selected from the groupconsisting of imidazo[1,5-a]pyridin-8-yl, imidazo[1,5-a]pyridin-6-yl,imidazo[1,5-a]pyridin-5-yl, imidazo[1,2-a]pyridin-8-yl,imidazo[1,2-a]pyridin-7-yl, imidazo[1,2-a]pyridin-6-yl,imidazo[1,2-a]pyridin-5-yl, imidazo[1,2-a]pyridin-3-yl,8-methylimidazo[1,2-a]pyridin-2-yl, indazol-4-yl,pyrrolo[2,3-b]pyridin-4-yl, pyrrolo[1,2-a]pyrazin-6-yl,pyrrolo[1,2-a]pyrazin-4-yl, pyrazolo[3,4-b]pyridin-4-yl,pyrazolo[1,5-a]pyrazin-3-yl, and quinolin-5-yl, each of which isoptionally substituted with one to three R^(a).
 48. The method of claim47, wherein: R² is selected from the group consisting of H and OR^(d);R³ is selected from the group consisting of H, CN, halo, and OR^(d); R⁴is selected from the group consisting of H, CN, and OR^(d): and R⁵ is H.49. The method of claim 23, wherein Q is selected from the groupconsisting of pyridin-3-yl and piperidin-1-yl, each of which isoptionally substituted with one to three R^(a).
 50. The method of claim49, wherein R⁵ is selected from the group consisting of hydroxy andfluoro.
 51. The method of claim 23, wherein the compound or a tautomeror pharmaceutically acceptable salt thereof, is selected from the groupconsisting of:2-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-5-methoxy-benzaldehyde,2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-benzaldehyde,2-hydroxy-6-((2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)pyridin-3-yl)-methoxy)benzaldehyde,2-hydroxy-6-((2-(1-(3,3,3-trifluoropropyl)-1H-pyrazol-5-yl)pyridin-3-yl)-methoxy)benzaldehyde,2-fluoro-6-((2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)pyridin-3-yl)-methoxy)benzaldehyde,2-fluoro-6-((2-(1-(3,3,3-trifluoropropyl)-1H-pyrazol-5-yl)pyridin-3-yl)-methoxy)benzaldehyde,and2-fluoro-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-benzaldehyde,or a tautomer or pharmaceutically acceptable salt thereof.
 52. Themethod of claim 23, wherein the compound is2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-benzaldehyde,or a tautomer or a pharmaceutically acceptable salt thereof.
 53. Themethod of claim 52, wherein the compound is2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde.